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Entry
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- *300300 - BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300300</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300300">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000010671;t=ENST00000308731" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=695" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300300" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000010671;t=ENST00000308731" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000061,NM_001287344,NM_001287345" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000061" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300300" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02248&isoform_id=02248_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/BTK" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/312467,517438,547759,632960,1684918,4557377,7157905,7157907,7157909,7157911,7157913,7157915,7157917,7157919,7157921,7157923,7381350,62147583,62147585,62147587,62147589,62147591,62147593,71668486,76057621,76057623,76057625,76057627,76057629,76057631,76057633,76057635,76057637,76057639,76057641,76057643,80478105,80478110,119623261,119623262,119623263,189067298,193787041,545560960,565324225,565324227,2193966224" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q06187" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=695" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000010671;t=ENST00000308731" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=BTK" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=BTK" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+695" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/BTK" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:695" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/695" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000308731.8&hgg_start=101349450&hgg_end=101390796&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1133" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1133" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/btk" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300300[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300300[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000010671" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=BTK" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=BTK" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BTK" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/BTKbase/" title="BTK base: Mutation registry for X-linked agammaglobulinemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">BTK base: Mutation registr…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/BTK" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">BTK database at LOVD</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BTK&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA25454" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1133" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003502.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88216" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/BTK#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:88216" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/695/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=695" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070531-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:300300" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:695" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=BTK&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 234533006, 65880007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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300300
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
AGAMMAGLOBULINEMIA TYROSINE KINASE; ATK<br />
|
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B-CELL PROGENITOR KINASE; BPK
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BTK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BTK</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/X/500?start=-3&limit=10&highlight=500">Xq22.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:101349450-101390796&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:101,349,450-101,390,796</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300755,307200" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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Agammaglobulinemia, X-linked 1
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Isolated growth hormone deficiency, type III, with agammaglobulinemia
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/300300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/300300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>BTK is a key regulator of B-cell development (<a href="#37" class="mim-tip-reference" title="Rawlings, D. J., Witte, O. N. <strong>Bruton's tyrosine kinase is a key regulator in B-cell development.</strong> Immun. Rev. 138: 105-119, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8070812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8070812</a>] [<a href="https://doi.org/10.1111/j.1600-065x.1994.tb00849.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8070812">Rawlings and Witte, 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8070812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a positional cloning strategy to identify genes within the XLA locus on the X chromosome, followed by screening a cDNA library derived from a Burkitt lymphoma cell line, <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> isolated BTK, which they called ATK. The ORF of ATK encodes a 659-amino acid polypeptide. Two alternative initiation codons within the same ORF would result in peptide chains of 571 and 497 amino acids, respectively, if used. ATK shares a high degree of similarity with members of the SRC (<a href="/entry/190090">190090</a>) family of protooncogenes that encode protein-tyrosine kinases. Northern blot analysis of RNAs derived from lymphoid lineages demonstrated that the 2.6-kb ATK mRNA was expressed in a B-cell line and in B cells of 2 patients with chronic lymphocytic leukemia, but not in T cells or a T-cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8380905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Desiderio, S. <strong>Becoming B cells. (Abstract)</strong> Nature 361: 202, 1993."None>Desiderio (1993)</a> compared the structure of ATK and LTK (<a href="/entry/151520">151520</a>) with SRC.</p><p><a href="#44" class="mim-tip-reference" title="Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., Witte, O. N. <strong>Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.</strong> Cell 72: 279-290, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8425221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8425221</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90667-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8425221">Tsukada et al. (1993)</a> independently described BTK as a cytoplasmic tyrosine kinase that they termed BPK. BPK was expressed in all cells of the B lineage and in myeloid cells. <a href="#44" class="mim-tip-reference" title="Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., Witte, O. N. <strong>Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.</strong> Cell 72: 279-290, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8425221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8425221</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90667-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8425221">Tsukada et al. (1993)</a> concluded that BPK is not a member of the SRC family based on the following differences: (1) the kinase catalytic domain contains the sequence DLAARN, which is similar to ABL (<a href="/entry/189980">189980</a>), FPS (<a href="/entry/190030">190030</a>), and CSK (<a href="/entry/124095">124095</a>), but different from the SRC family (DLRAAN); (2) BPK lacks the consensus myristoylation signal (glycine at position 2 and lysine or arginine at position 7); (3) BPK lacks the equivalent of tyrosine 527 in SRC in the C-terminal domain following the kinase sequences, which is important in regulation of kinase activity; and (4) the N-terminal region of BPK is unusually long. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8425221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Gene Structure</strong>
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<p><a href="#38" class="mim-tip-reference" title="Rohrer, J., Parolini, O., Belmont, J. W., Conley, M. E. <strong>The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia.</strong> Immunogenetics 40: 319-324, 1994. Note: Erratum: Immunogenetics 42: 76 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7927535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7927535</a>] [<a href="https://doi.org/10.1007/BF01246672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7927535">Rohrer et al. (1994)</a> determined the genomic organization of the BTK gene. BTK contains 19 exons and spans 37 kb. The region 5-prime to the first untranslated exon lacks TATAA or CAAT boxes, but it contains 3 retinoic acid-binding sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7927535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By in situ hybridization, <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> mapped the BTK gene to chromosome Xq21.3-q22. <a href="#33" class="mim-tip-reference" title="Oeltjen, J. C., Liu, X., Lu, J., Allen, R. C., Muzny, D., Belmont, J. W., Gibbs, R. A. <strong>Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci.</strong> Mammalian Genome 6: 334-338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7626884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7626884</a>] [<a href="https://doi.org/10.1007/BF00364796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7626884">Oeltjen et al. (1995)</a> concluded that the 3-prime end of the GLA gene (<a href="/entry/300644">300644</a>) is 9 kb from the 5-prime end of the BTK gene, and they found 2 additional genes in the region immediately 5-prime to BTK. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8380905+7626884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#44" class="mim-tip-reference" title="Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., Witte, O. N. <strong>Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.</strong> Cell 72: 279-290, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8425221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8425221</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90667-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8425221">Tsukada et al. (1993)</a> found that BPK mRNA, protein expression, and kinase activity were all reduced or absent in XLA pre-B and B cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8425221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although evidence from the study of XLA indicated that BTK plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remained unknown, primarily because the proteins that it interacts with had not been identified until the work of <a href="#6" class="mim-tip-reference" title="Cheng, G., Ye, Z.-S., Baltimore, D. <strong>Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.</strong> Proc. Nat. Acad. Sci. 91: 8152-8155, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8058772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8058772</a>] [<a href="https://doi.org/10.1073/pnas.91.17.8152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8058772">Cheng et al. (1994)</a>. They showed that BTK interacted with SRC homology 3 domains of FYN (<a href="/entry/137025">137025</a>), LYN (<a href="/entry/165120">165120</a>), and HCK (<a href="/entry/142370">142370</a>). All of these are protein-tyrosine kinases that are activated upon stimulation of B- and T-cell receptors. These interactions were mediated by two 10-amino acid motifs in BTK. An analogous site with the same specificity was also identified in ITK (<a href="/entry/186973">186973</a>), the T-cell-specific homolog of BTK. The findings of <a href="#6" class="mim-tip-reference" title="Cheng, G., Ye, Z.-S., Baltimore, D. <strong>Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.</strong> Proc. Nat. Acad. Sci. 91: 8152-8155, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8058772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8058772</a>] [<a href="https://doi.org/10.1073/pnas.91.17.8152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8058772">Cheng et al. (1994)</a> extended the range of interactions mediated by SRC homology 3 domains and provided an indication of a link between BTK and previously established signaling pathways in B lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8058772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Uckun, F. M., Waddick, K. G., Mahajan, S., Jun, X., Takata, M., Bolen, J., Kurosaki, T. <strong>BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells.</strong> Science 273: 1096-1099, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8688094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8688094</a>] [<a href="https://doi.org/10.1126/science.273.5278.1096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8688094">Uckun et al. (1996)</a> noted that a number of human diseases including immune deficiencies apparently stem from inherited or acquired deficiencies of checkpoints that regulate the rate of apoptosis in lymphoid cells. <a href="#45" class="mim-tip-reference" title="Uckun, F. M., Waddick, K. G., Mahajan, S., Jun, X., Takata, M., Bolen, J., Kurosaki, T. <strong>BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells.</strong> Science 273: 1096-1099, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8688094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8688094</a>] [<a href="https://doi.org/10.1126/science.273.5278.1096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8688094">Uckun et al. (1996)</a> reported that DT-40 lymphoma B cells rendered BTK deficient through targeted disruption of the BTK gene did not undergo radiation-induced apoptosis. They further demonstrated that the tyrosine kinase domain of BTK was necessary for triggering radiation-induced apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8688094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Ng, Y.-S., Wardemann, H., Chelnis, J., Cunningham-Rundles, C., Meffre, E. <strong>Bruton's tyrosine kinase is essential for human B cell tolerance.</strong> J. Exp. Med. 200: 927-934, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466623[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20040920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466623">Ng et al. (2004)</a> tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients with XLA and found that XLA B cells were selected to express a unique antibody repertoire using distinct VH and D genes favoring hydrophobic reading frames normally counterselected in healthy donor B cells. Patient B cells appeared to undergo extensive secondary recombination on both IgK (see <a href="/entry/147200">147200</a>) and IgL (see <a href="/entry/147220">147220</a>) loci and had a slightly increased proportion of cells expressing antinuclear antibodies. <a href="#32" class="mim-tip-reference" title="Ng, Y.-S., Wardemann, H., Chelnis, J., Cunningham-Rundles, C., Meffre, E. <strong>Bruton's tyrosine kinase is essential for human B cell tolerance.</strong> J. Exp. Med. 200: 927-934, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466623[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20040920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466623">Ng et al. (2004)</a> concluded that almost half of the antibodies expressed by XLA B cells are polyreactive and that BTK is essential for removal of autoreactive B cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Hantschel, O., Rix, U., Schmidt, U., Burckstummer, T., Kneidinger, M., Schutze, G., Colinge, J., Bennett, K. L., Ellmeier, W., Valent, P., Superti-Furga, G. <strong>The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib.</strong> Proc. Nat. Acad. Sci. 104: 13283-13288, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17684099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17684099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17684099[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0702654104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17684099">Hantschel et al. (2007)</a> identified the BTK tyrosine kinase and TEC kinase (<a href="/entry/600583">600583</a>) as major binders of the tyrosine kinase inhibitor dasatinib, which is used for treatment of BCR/ABL (see <a href="/entry/151410">151410</a>)-positive CML (<a href="/entry/608232">608232</a>). Dasatinib did not bind ITK. In a CML cell line, they determined that a thr474-to-ile (T474I) substitution in the BTK gene conferred resistance to dasatinib. They suggested that, like the structurally homologous thr315 residue in the ABL gene (see <a href="/entry/189980#0001">189980.0001</a>), the BTK thr474 residue is the gatekeeper residue critical for dasatinib binding. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The findings suggested that dasatinib may have immunosuppressive side effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17684099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using ELISA, microarray analysis, RT-PCR, and flow cytometry, <a href="#20" class="mim-tip-reference" title="Hasan, M., Lopez-Herrera, G., Blomberg, K. E. M., Lindvall, J. M., Berglof, A., Smith, C. I. E., Vargas, L. <strong>Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice.</strong> Immunology 123: 239-249, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17725607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17725607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17725607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2007.02693.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17725607">Hasan et al. (2007)</a> demonstrated that Btk -/- mouse B cells responded more efficiently to CpG-DNA stimulation by producing higher levels of proinflammatory cytokines and Il27 (<a href="/entry/608273">608273</a>), but lower levels of the inhibitory cytokine Il10 (<a href="/entry/124092">124092</a>). Tlr9 (<a href="/entry/605474">605474</a>) protein and mRNA expression was enhanced in Btk -/- cells, especially after Tlr9 stimulation. Whereas Btk -/- and wildtype transitional stage-1 (T1) B cells failed to proliferate and died after CpG stimulation, T2 cells, expressing higher levels of Tlr9, proliferated and matured. <a href="#20" class="mim-tip-reference" title="Hasan, M., Lopez-Herrera, G., Blomberg, K. E. M., Lindvall, J. M., Berglof, A., Smith, C. I. E., Vargas, L. <strong>Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice.</strong> Immunology 123: 239-249, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17725607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17725607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17725607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2007.02693.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17725607">Hasan et al. (2007)</a> concluded that BTK regulates both TLR9 activation and expression in B lymphocytes and is necessary for inhibitory cytokine expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17725607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using bone marrow-derived macrophages (BMDMs) from mice and humans with genetic BTK deficiency, <a href="#28" class="mim-tip-reference" title="Mao, L., Kitani, A., Hiejima, E., Montgomery-Recht, K., Zhou, W., Fuss, I., Wiestner, A., Strober, W. <strong>Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1-beta-mediated colitis.</strong> J. Clin. Invest. 130: 1793-1807, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31895698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31895698</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31895698[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI128322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31895698">Mao et al. (2020)</a> found that BTK regulated NLRP3 (<a href="/entry/606416">606416</a>) inflammasome activation, but not other inflammasomes. Similarly, exposure to low concentrations of a BTK inhibitor upregulated NLRP3 inflammasome activity, whereas high concentrations of the inhibitor caused BTK-independent inhibition of NLRP3 inflammasome activity. Overexpression and knockout analyses revealed that BTK interacted with NLRP3 and regulated its phosphorylation and oligomerization, thereby modulating NLRP3 inflammasome activation. In addition, BTK downregulated NLRP3 interaction with ASC (PYCARD; <a href="/entry/606838">606838</a>) and ASC assembly. BTK also inhibited NLRP3 interaction with NEK7 (<a href="/entry/606848">606848</a>), thereby inhibiting NEK7 phosphorylation and oligomerization. Mutation analysis showed that the PH and PTK domains of BTK interacted with the pyrin and NACHT domains of NLRP3. The PTK domain containing the BTK kinase site played a critical role in BTK inhibition of the NLRP3 inflammasome, as BTK kinase activity was required for its inhibitory function. BTK interacted with protein PP2A (PPP2CA; <a href="/entry/176915">176915</a>) and upregulated PP2A phosphorylation at tyr307. Phosphorylation of PP2A temporarily inactivated PP2A and prevented it from dephosphorylating ser5 in the NLRP3 pyrin domain, leading to inhibition of the NLRP3 inflammasome. Further analysis demonstrated that the different dosage-dependent effects of BTK inhibitors on NLRP3 inflammasome activity were due to the differential effects of the inhibitors on the interaction of NLRP3 with its downstream NLRP3 inflammasome components and on the generation of NLRP3 inflammasome products. Inhibition of the NLRP3 inflammasome by high-dose BTK inhibitor was likely an off-target effect of the inhibitors on JNK (<a href="/entry/601158">601158</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31895698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#51" class="mim-tip-reference" title="Vihinen, M., Vetrie, D., Maniar, H. S., Ochs, H. D., Zhu, Q., Vorechovsky, I., Webster, A. D. B., Notarangelo, L. D., Nilsson, L., Sowadski, J. M., Smith, C. I. E. <strong>Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.</strong> Proc. Nat. Acad. Sci. 91: 12803-12807, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7809124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7809124</a>] [<a href="https://doi.org/10.1073/pnas.91.26.12803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7809124">Vihinen et al. (1994)</a> used a 3-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, to interpret the structural basis for disease in 8 independent point mutations in patients with XLA. Because arg525 of BTK had been thought to substitute functionally for a critical lysine residue in protein-serine kinases, they studied the arg525-to-gln mutation and found that it abrogated the tyrosine kinase activity of BTK. All of the 8 mutations, including lys430-to-glu (<a href="#0002">300300.0002</a>), were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7809124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Mao, C., Zhou, M., Uckun, F. M. <strong>Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia.</strong> J. Biol. Chem. 276: 41435-41443, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11527964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11527964</a>] [<a href="https://doi.org/10.1074/jbc.M104828200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11527964">Mao et al. (2001)</a> determined the x-ray crystal structure of the BTK kinase domain in its unphosphorylated state to 2.1-angstrom resolution. The structure suggested that the trans-phosphorylation of tyr551 can lead to BTK activation by triggering an exchange of hydrogen-bonded pairs from glu445/arg544 to glu445/lys430 and subsequent relocation of helix alpha-C of the N-terminal lobe. The model also indicated that mutations in the C-terminal lobe of the kinase domain, such as R562W (<a href="#0042">300300.0042</a>), are directly or indirectly involved in peptide substrate binding. Other disease-associated mutations in this domain (e.g., E589G; <a href="#0044">300300.0044</a>) alter interactions with neighboring residues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11527964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>) is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. Using probes derived for the Southern analysis of DNA from 33 unrelated families and 150 normal X chromosomes, <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> detected restriction pattern abnormalities in 8 families with XLA. Five of them had deletions that were shown to be entirely intragenic to BTK, confirming involvement of BTK in XLA. Two single-base missense mutations were identified in XLA patients. The failure of pre-B cells in the bone marrow of XLA males to develop into mature, circulating B cells could be the result of the product of the mutant ATK gene failing to fulfill its role in B-cell signaling. <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> noted that inactivation of the mouse Lck gene (<a href="/entry/153390">153390</a>), another member of the SRC family of tyrosine kinases, results in a thymocyte differentiation defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8380905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Parolini, O., Hejtmancik, J. F., Allen, R. C., Belmont, J. W., Lassiter, G. L., Henry, M. J., Barker, D. F., Conley, M. E. <strong>Linkage analysis and physical mapping near the gene for X-linked agammaglobulinemia at Xq22.</strong> Genomics 15: 342-349, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8449500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8449500</a>] [<a href="https://doi.org/10.1006/geno.1993.1066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8449500">Parolini et al. (1993)</a> identified a family in which a healthy father transmitted the XLA defect to 2 of his daughters, indicating gonadal or somatic mosaicism. To assess the frequency of this phenomenon, <a href="#10" class="mim-tip-reference" title="Conley, M. E., Mathias, D., Treadaway, J., Minegishi, Y., Rohrer, J. <strong>Mutations in Btk in patients with presumed X-linked agammaglobulinemia.</strong> Am. J. Hum. Genet. 62: 1034-1043, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545398</a>] [<a href="https://doi.org/10.1086/301828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545398">Conley et al. (1998)</a> evaluated 11 sisters of 7 women who were carriers of XLA and whose mutation occurred on the paternal haplotype. None of the 11 sisters were carriers of the mutations seen in their nephews. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8449500+9545398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Vorechovsky, I., Zhou, J.-N., Vetrie, D., Bentley, D., Bjorkander, J., Hammarstrom, L., Smith, C. I. E. <strong>Molecular diagnosis of X-linked agammaglobulinaemia. (Letter)</strong> Lancet 341: 1153, 1993. Note: Erratum: Lancet 361: 1394 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097835</a>] [<a href="https://doi.org/10.1016/0140-6736(93)93172-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8097835">Vorechovsky et al. (1993)</a> pointed out that common variable immunodeficiency (CVID) is sometimes clinically and immunologically indistinguishable from XLA if it starts early in childhood and occurs sporadically in males with a decreased number of B cells. Using a cDNA clone that represented the full-length ATK (BTK) cDNA, <a href="#53" class="mim-tip-reference" title="Vorechovsky, I., Zhou, J.-N., Hammarstrom, L., Smith, C. I. E., Thomas, J. D., Paul, W. E., Notarangelo, L. D., Bernatowska-Matuszkiewicz, E. <strong>Absence of xid mutation in X-linked agammaglobulinaemia. (Letter)</strong> Lancet 342: 552, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102684</a>] [<a href="https://doi.org/10.1016/0140-6736(93)91676-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102684">Vorechovsky et al. (1993)</a> did Southern blot analysis of 39 Swedish male patients diagnosed with CVID or possible CVID. One man in his late 40s, who had had recurrent respiratory infections from infancy, lacked immunoglobulins of all isotypes, and had less than 1% B cells among peripheral blood mononuclear cells, had an abnormality of the ATK gene. The abnormality was missing in his mother but had been inherited by both of his daughters. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8102684+8097835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Vorechovsky, I., Zhou, J.-N., Hammarstrom, L., Smith, C. I. E., Thomas, J. D., Paul, W. E., Notarangelo, L. D., Bernatowska-Matuszkiewicz, E. <strong>Absence of xid mutation in X-linked agammaglobulinaemia. (Letter)</strong> Lancet 342: 552, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102684</a>] [<a href="https://doi.org/10.1016/0140-6736(93)91676-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102684">Vorechovsky et al. (1993)</a> failed to find the arg28-to-cys mutation, which is found in xid in mice (see ANIMAL MODEL), in 13 unrelated patients with XLA and 2 patients with XLA and growth hormone deficiency (IGHD3; <a href="/entry/307200">307200</a>). They pointed to the milder phenotype of the xid mouse compared to XLA cases and suggested that if this particular mutation occurs in the human BTK gene, it might result in a milder phenotype with normal or only moderately reduced B cells and more selective immunoglobulin deficiency in boys, which may or may not increase susceptibility to infections. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8102684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Ohta, Y., Haire, R. N., Litman, R. T., Fu, S. M., Nelson, R. P., Kratz, J., Kornfeld, S. J., de la Morena, M., Good, R. A., Litman, G. W. <strong>Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.</strong> Proc. Nat. Acad. Sci. 91: 9062-9066, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8090769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8090769</a>] [<a href="https://doi.org/10.1073/pnas.91.19.9062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8090769">Ohta et al. (1994)</a> reported the DNA sequence of the 18 coding exons of BTK and their flanking regions. Correlations were made between the nature of mutations and the organization of the BTK gene. They found several examples of the same mutation occurring in unrelated patients, and one of these mutations occurred at the same codon that is substituted in the xid mouse. However, in xid, the mutation occurs at the first position in the conserved arginine codon, 214C-T, and results in an arg28-to-cys substitution, whereas in human cases it occurs at the second nucleotide, 215G-A, and results in an arg28-to-his amino acid change (<a href="#0005">300300.0005</a>). The observations suggested that a limited number of deleterious changes in BTK produce clinically recognizable XLA. XLA patients have been classified in 2 general groups: those presenting at an early age with particularly severe infections and those with less severe disease in which production of immunoglobulin is sustained at low-to-normal levels well into the first decade of life. In the latter cases, an oncogenetic change may occur in which the defective tyrosine kinase no longer can sustain the B-cell population, and a progressive reduction in immunoglobulin production occurs. <a href="#34" class="mim-tip-reference" title="Ohta, Y., Haire, R. N., Litman, R. T., Fu, S. M., Nelson, R. P., Kratz, J., Kornfeld, S. J., de la Morena, M., Good, R. A., Litman, G. W. <strong>Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.</strong> Proc. Nat. Acad. Sci. 91: 9062-9066, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8090769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8090769</a>] [<a href="https://doi.org/10.1073/pnas.91.19.9062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8090769">Ohta et al. (1994)</a> described the arg525-to-gln mutation (<a href="#0001">300300.0001</a>) in patients whose disorder might have been classified as common variable immunodeficiency disease. These patients had low levels of circulating B cells at an early age with mildly decreased IgM and variable IgG levels, although all were IgA deficient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8090769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Kornfeld, S. J., Kratz, J., Haire, R. N., Litman, G. W., Good, R. A. <strong>X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy.</strong> J. Allergy Clin. Immun. 95: 915-917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7722175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7722175</a>] [<a href="https://doi.org/10.1016/s0091-6749(95)70138-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7722175">Kornfeld et al. (1995)</a> described the case of a 16-year-old boy who had recurrent upper respiratory tract infections at 13 months of age and was diagnosed as having transient hypogammaglobulinemia of infancy on the basis of low immunoglobulin levels, normal diphtheria and tetanus antibody responses, normal anterior and posterior cervical nodes, normal tonsillar tissue, and normal numbers of B cells in the blood. IgA levels returned to normal at 15 months of age and remained within normal limits over the next 12 months, and IgG and IgM levels remained relatively unchanged. At age 10, he began receiving intravenous gammaglobulin, which resulted in cessation of infections. The clinical picture was thought to be that of common variable immunodeficiency disease. However, gene studies revealed the deletion of exon 16 of the BTK gene resulting from a splice junction defect. The patient represents an example of the extreme variation that can occur in the XLA phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7722175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Hagemann, T. L., Rosen, F. S., Kwan, S.-P. <strong>Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia.</strong> Hum. Mutat. 5: 296-302, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7627183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7627183</a>] [<a href="https://doi.org/10.1002/humu.1380050405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7627183">Hagemann et al. (1995)</a> described 6 mutations in the BTK gene as the cause of XLA; 5 were novel. The mutations included 2 nonsense and 2 missense mutations, a single base deletion at an intron acceptor splice site, and a 16-bp insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7627183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Kobayashi, S., Iwata, T., Saito, M., Iwasaki, R., Matsumoto, H., Naritaka, S., Kono, Y., Hayashi, Y. <strong>Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan.</strong> Hum. Genet. 97: 424-430, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8834236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8834236</a>]" pmid="8834236">Kobayashi et al. (1996)</a> reported abnormalities in the BTK gene in 12 unrelated Japanese families with X-linked agammaglobulinemia. Gene rearrangement in the kinase domain was found in 2 patients by Southern blotting. Seven point mutations, 2 small deletions, and 1 small insertion were detected by SSCP analysis and sequencing. Phenotypic heterogeneity was observed in affected family members with the same mutation. The authors concluded that analyzing BTK gene alterations with SSCP is valuable for the diagnosis of XLA patients and for carrier detection; however, the correlation between gene abnormalities and clinical features remains unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8834236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 26 unrelated patients with XLA, <a href="#52" class="mim-tip-reference" title="Vorechovsky, I., Luo, L., Hertz, J. M., Froland, S. S., Klemola, T., Fiorini, M., Quinti, I., Paganelli, R., Ozsahin, H., Hammarstrom, L., Webster, A. D. B., Smith, C. I. E. <strong>Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia.</strong> Hum. Mutat. 9: 418-425, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143921</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<418::AID-HUMU7>3.0.CO;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143921">Vorechovsky et al. (1997)</a> found 24 different mutations of the BTK gene. Most resulted in the premature termination of translation. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5-prime end of the gene and missense mutations in its 3-prime part, corresponding to the catalytic domain of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9143921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Conley, M. E., Mathias, D., Treadaway, J., Minegishi, Y., Rohrer, J. <strong>Mutations in Btk in patients with presumed X-linked agammaglobulinemia.</strong> Am. J. Hum. Genet. 62: 1034-1043, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545398</a>] [<a href="https://doi.org/10.1086/301828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545398">Conley et al. (1998)</a> analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in the BTK gene were identified in 38 of 40 families with more than 1 affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in BTK were identified in 43 of 46 patients with presumed sporadic XLA. Two of the 3 remaining patients had defects in other genes required for normal B cell development, namely the mu heavy chain gene (IGHM1; <a href="/entry/147020">147020</a>), as reported by <a href="#57" class="mim-tip-reference" title="Yel, L., Minegishi, Y., Coustan-Smith, E., Buckley, R. H., Trubel, H., Pachman, L. M., Kitchingman, G. R., Campana, D., Rohrer, J., Conley, M. E. <strong>Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.</strong> New Eng. J. Med. 335: 1486-1493, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8890099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8890099</a>] [<a href="https://doi.org/10.1056/NEJM199611143352003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8890099">Yel et al. (1996)</a> or the lambda-5/14.1 surrogate light chain gene (IGLL1; <a href="/entry/146770">146770</a>), as reported by <a href="#31" class="mim-tip-reference" title="Minegishi, Y., Coustan-Smith, E., Wang, Y.-H., Cooper, M. D., Campana, D., Conley, M. E. <strong>Mutations in the human lambda-5/14.1 gene result in B cell deficiency and agammaglobulinemia.</strong> J. Exp. Med. 187: 71-77, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9419212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9419212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9419212[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.187.1.71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9419212">Minegishi et al. (1998)</a>. Both of these patients were compound heterozygotes and there were no clinical features that would distinguish them from patients with typical XLA. An Epstein-Barr virus-transformed cell line from a third patient had normal BTK cDNA by SSCP, normal BTK message by Northern blot, and normal BTK protein by Western blot. Therefore, it is unlikely that this patient had XLA. Ten mutations were found in more than one family; 1 of these occurred in 3 families. Of the 83 unique mutations included in the study of <a href="#10" class="mim-tip-reference" title="Conley, M. E., Mathias, D., Treadaway, J., Minegishi, Y., Rohrer, J. <strong>Mutations in Btk in patients with presumed X-linked agammaglobulinemia.</strong> Am. J. Hum. Genet. 62: 1034-1043, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545398</a>] [<a href="https://doi.org/10.1086/301828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545398">Conley et al. (1998)</a>, 43 had been described previously by their laboratory, 5 had been reported by other groups, and 35 had not been previously described. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8890099+9545398+9419212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 12 Korean patients with X-linked agammaglobulinemia, <a href="#21" class="mim-tip-reference" title="Jo, E.-K., Kanegane, H., Nonoyama, S., Tsukada, S., Lee, J.-H., Lim, K., Shong, M., Song, C.-H., Kim, H.-J., Park, J.-K., Miyawaki, T. <strong>Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase gene from seven Korean X-linked agammaglobulinemia families.</strong> J. Immun. 167: 4038-4045, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564824</a>] [<a href="https://doi.org/10.4049/jimmunol.167.7.4038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564824">Jo et al. (2001)</a> identified 7 mutations in the BTK gene, including a point mutation in intron 1 (<a href="#0055">300300.0055</a>). Luciferase analysis showed reduced transcriptional activity in the intron-1 mutant compared with the wildtype. EMSA and functional analysis indicated that a nuclear protein had the ability to bind to the intron-1 mutant oligonucleotides. <a href="#21" class="mim-tip-reference" title="Jo, E.-K., Kanegane, H., Nonoyama, S., Tsukada, S., Lee, J.-H., Lim, K., Shong, M., Song, C.-H., Kim, H.-J., Park, J.-K., Miyawaki, T. <strong>Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase gene from seven Korean X-linked agammaglobulinemia families.</strong> J. Immun. 167: 4038-4045, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564824</a>] [<a href="https://doi.org/10.4049/jimmunol.167.7.4038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564824">Jo et al. (2001)</a> proposed that several regulatory elements mediate the transcriptional regulation of BTK and that the first intron is important in BTK promoter activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11564824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Sakamoto, M., Kanegane, H., Fujii, H., Tsukada, S., Miyawaki, T., Shinomiya, N. <strong>Maternal germinal mosaicism of X-linked agammaglobulinemia.</strong> Am. J. Med. Genet. 99: 234-237, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11241495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11241495</a>] [<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1159>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11241495">Sakamoto et al. (2001)</a> suggested maternal germinal mosaicism to explain the finding of 2 sibs with XLA who had a single base deletion (563C) in exon 6 of the BTK gene and whose mother had no evidence of the mutation. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient; normal cytoplasmic expression of BTK protein was found in monocytes of the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11241495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., Roep, B. O. <strong>Development of type 1 diabetes despite severe hereditary B-cell deficiency.</strong> New Eng. J. Med. 345: 1036-1040, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586956</a>] [<a href="https://doi.org/10.1056/NEJMoa010465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586956">Martin et al. (2001)</a> identified a 2-bp deletion in the BTK gene (<a href="#0054">300300.0054</a>) in a patient with X-linked agammaglobulinemia who developed classic type I diabetes (see <a href="/entry/222100">222100</a>) at the age of 14 years. Autoantibodies associated with type I diabetes were undetectable, a result consistent with the diagnosis of X-linked agammaglobulinemia. The patient's HLA type was the one that is associated with the highest genetic risk of type I diabetes. The data implied that autoantibodies are not required for either the initiation or the progression of type I diabetes. <a href="#30" class="mim-tip-reference" title="Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., Roep, B. O. <strong>Development of type 1 diabetes despite severe hereditary B-cell deficiency.</strong> New Eng. J. Med. 345: 1036-1040, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586956</a>] [<a href="https://doi.org/10.1056/NEJMoa010465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586956">Martin et al. (2001)</a> concluded that type I diabetes can develop in the absence of both autoantibodies and B cells. This aspect of its pathogenesis places type I diabetes in marked contrast to spontaneous autoimmune diabetes in NOD mice, which has been claimed to be B cell-dependent. The findings suggested that immunotherapy directed specifically toward B cells or autoantibodies may not be effective in preventing the destruction of beta cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Wattanasirichaigoon, D., Benjaponpitak, S., Techasaensiri, C., Kamchaisatian, W., Vichyanond, P., Janwityanujit, S., Choubtum, L., Sirinavin, S. <strong>Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations.</strong> J. Hum. Genet. 51: 1006-1014, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951917</a>] [<a href="https://doi.org/10.1007/s10038-006-0052-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16951917">Wattanasirichaigoon et al. (2006)</a> reported 7 different mutations in the BTK gene among 7 patients with XLA; 4 of the mutations were novel. Six patients were Thai, and 1 patient was Burmese. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>About 60% of DCLRE1C (<a href="/entry/605988">605988</a>) and IGHM (<a href="/entry/147020">147020</a>) gene defects involve gross deletions, compared with about 6% of BTK gene defects. <a href="#47" class="mim-tip-reference" title="van Zelm, M. C., Geertsema, C., Nieuwenhuis, N., de Ridder, D., Conley, M. E., Schiff, C., Tezcan, I., Bernatowska, E., Hartwig, N. G., Sanders, E. A. M., Litzman, J., Kondratenko, I., van Dongen, J. J. M., van der Burg, M. <strong>Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements.</strong> Am. J. Hum. Genet. 82: 320-332, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252213[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.10.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252213">Van Zelm et al. (2008)</a> compared gross deletion breakpoints involving DCLRE1C, IGHM, and BTK to identify mechanisms underlying these differences in gross deletion frequencies. Their analysis suggested that gross deletions involve transposable elements or large homologous regions rather than recombination motifs. <a href="#47" class="mim-tip-reference" title="van Zelm, M. C., Geertsema, C., Nieuwenhuis, N., de Ridder, D., Conley, M. E., Schiff, C., Tezcan, I., Bernatowska, E., Hartwig, N. G., Sanders, E. A. M., Litzman, J., Kondratenko, I., van Dongen, J. J. M., van der Burg, M. <strong>Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements.</strong> Am. J. Hum. Genet. 82: 320-332, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252213[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.10.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252213">Van Zelm et al. (2008)</a> hypothesized that the transposable element content of a gene is related to its gross deletion frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Isolated Growth Hormone Deficiency III with Agammaglobulinemia</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. <strong>An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency.</strong> FEBS Lett. 346: 165-170, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8013627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8013627</a>] [<a href="https://doi.org/10.1016/0014-5793(94)00457-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8013627">Duriez et al. (1994)</a> found an exon-skipping mutation (<a href="#0004">300300.0004</a>) in the BTK gene in a sporadic case of X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; <a href="/entry/307200">307200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8013627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with growth hormone deficiency and agammaglobulinemia (patients 14 and 19), previously reported by <a href="#8" class="mim-tip-reference" title="Conley, M. E., Burks, A. W., Herrod, H. G., Puck, J. M. <strong>Molecular analysis of X-linked agammaglobulinemia with growth hormone deficiency.</strong> J. Pediat. 119: 392-397, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1880652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1880652</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)82051-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1880652">Conley et al. (1991)</a>, <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified mutations in the BTK gene, Y375X (<a href="#0030">300300.0030</a>) and L542P (<a href="#0040">300300.0040</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7849697+1880652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>BTK Mutation Database</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Vihinen, M., Iwata, T., Kinnon, C., Kwan, S.-P., Ochs, H. D., Vorechovsky, I., Smith, C. I. E. <strong>BTKbase, mutation database for X-linked agammaglobulinemia (XLA).</strong> Nucleic Acids Res. 24: 160-165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8594569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8594569</a>] [<a href="https://doi.org/10.1093/nar/24.1.160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8594569">Vihinen et al. (1996)</a> described a database of BTK mutations (BTKbase) listing entries from 189 unrelated families showing 148 unique molecular events. Information was included regarding the phenotype. Mutations in all 5 domains of BTK had been observed to cause XLA, the most common class of changes being missense mutations. The mutations appeared almost uniformly throughout the molecule and frequently affected CpG sites forming arginine residues. <a href="#50" class="mim-tip-reference" title="Vihinen, M., Kwan, S.-P., Lester, T., Ochs, H. D., Resnick, I., Valiaho, J., Conley, M. E., Smith, C. I. E. <strong>Mutations of the human BTK gene coding for Bruton tyrosine kinase in X-linked agammaglobulinemia.</strong> Hum. Mutat. 13: 280-285, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220140</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<280::AID-HUMU3>3.0.CO;2-L" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220140">Vihinen et al. (1999)</a> reported that BTKbase listed 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms had been found. Most mutations led to truncation of the enzyme, and about one-third of point mutations affected CpG sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10220140+8594569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Presumably the X-linked B-lymphocyte defect of mice, studied by <a href="#29" class="mim-tip-reference" title="Marshall-Clarke, S., Cooke, A., Hutchings, P. R. <strong>Deficient production of anti-red cell autoantibodies by mice with an X-linked B-lymphocyte defect.</strong> Europ. J. Immun. 9: 820-823, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/316393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">316393</a>] [<a href="https://doi.org/10.1002/eji.1830091014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="316393">Marshall-Clarke et al. (1979)</a>, is homologous. This defect is characteristic of the CBA-N strain of mice (<a href="#41" class="mim-tip-reference" title="Scher, I., Steinberg, A. D., Berning, A. K., Paul, W. E. <strong>X-linked B-lymphocyte immune defect in CBA-N mice. II. Studies of the mechanisms underlying the immune defect.</strong> J. Exp. Med. 142: 637-650, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1080788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1080788</a>] [<a href="https://doi.org/10.1084/jem.142.3.637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1080788">Scher et al., 1975</a>). Defective mice lack the subpopulation of B lymphocytes responsive to certain T-independent antigens of which trinitrophenylated (TNP)-Ficoll is the prototype. Their responses to T-dependent antigens may also be impaired and they are unable to respond to the hapten phosphorylcholine (PC). They lack those B cells that form colonies when cultured in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=316393+1080788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Cohen, D. I., Steinberg, A. D., Paul, W. E., Davis, M. M. <strong>Expression of an X-linked gene family (XLR) in late-stage B cells and its alteration by the xid mutation..</strong> Nature 314: 372-374, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3872416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3872416</a>] [<a href="https://doi.org/10.1038/314372a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3872416">Cohen et al. (1985)</a> isolated a cDNA probe recognizing a family of genes, called XLR, on the mouse X chromosome, at least some members of which are closely linked to the X-linked immunodeficiency (xid) trait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3872416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Linkage studies involving 1,114 progeny backcross revealed colocalization of the xid mutation in mice with the Btk gene (<a href="#43" class="mim-tip-reference" title="Thomas, J. D., Sideras, P., Smith, C. I. E., Vorechovsky, I., Chapman, V., Paul, W. E. <strong>Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes.</strong> Science 261: 355-358, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8332900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8332900</a>] [<a href="https://doi.org/10.1126/science.8332900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8332900">Thomas et al., 1993</a>). The xid mutation was associated in mice with a missense mutation that altered the highly conserved arginine near the N terminus of the Btk protein. Because this region of the protein lies outside any obvious kinase domain, the xid mutation may define another aspect of tyrosine kinase. <a href="#36" class="mim-tip-reference" title="Rawlings, D. J., Saffran, D. C., Tsukada, S., Largaespada, D. A., Grimaldi, J. C., Cohen, L., Mohr, R. N., Bazan, J. F., Howard, M., Copeland, N. G., Jenkins, N. A., Witte, O. N. <strong>Mutation of unique region of Bruton's tyrosine kinase in immunodeficient xid mice.</strong> Science 261: 358-361, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8332901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8332901</a>] [<a href="https://doi.org/10.1126/science.8332901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8332901">Rawlings et al. (1993)</a> likewise mapped the xid and the Btk gene to the same region and demonstrated the same missense mutation, an arg28-to-cys change. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8332901+8332900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Drabek, D., Raguz, S., De Wit, T. P. M., Dingjan, G. M., Savelkoul, H. F. J., Grosveld, F., Hendriks, R. W. <strong>Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region.</strong> Proc. Nat. Acad. Sci. 94: 610-615, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9012832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.2.610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9012832">Drabek et al. (1997)</a> generated transgenic mice in which expression of the human BTK gene was driven by the murine class II major histocompatibility complex Ea gene locus control region, which provides gene expression from the pre-B cell stage onwards. When these transgenic mice were mated onto a Btk(-) background, correction of the xid B cell defects was observed: B cells differentiated to mature low IgM/high IgD stages, peritoneal CD5(+) B cells were present, and serum immunoglobulin levels and in vivo responses to antigens were in the normal ranges. A comparable rescue by transgenic Btk expression was also observed in heterozygous Btk +/- female mice in those B-lineage cells that were Btk-deficient as a result of X-chromosome inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9012832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Kawakami, Y., Inagaki, N., Salek-Ardakani, S., Kitaura, J., Tanaka, H., Nagao, K., Kawakami, Y., Xiao, W., Nagai, H., Croft, M., Kawakami, T. <strong>Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3.</strong> Proc. Nat. Acad. Sci. 103: 153-158, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16371463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16371463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16371463[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0509784103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16371463">Kawakami et al. (2006)</a> found that dendritic cells of Btk-null mice exhibited a more mature phenotype and a stronger in vitro and in vivo T cell-stimulatory ability than wildtype cells. Increased IgE responses were induced by adoptive transfer of Btk-null dendritic cells into wildtype mice. Consistent with the stronger T cell-stimulatory ability of Btk-null dendritic cells, Btk-null mice exhibited enhanced inflammation in T helper cell 2-driven asthma and T helper cell 1-driven contact sensitivity experiments. The negative regulatory functions of Btk in dendritic cells appeared to be mediated mainly through autocrine secretion of IL10 (<a href="/entry/124092">124092</a>) and subsequent activation of Stat3 (<a href="/entry/102582">102582</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16371463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Tec (<a href="/entry/600583">600583</a>) -/- Btk -/- double-knockout mice, <a href="#42" class="mim-tip-reference" title="Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., Takai, T., Kodama, T., Morio, T., Geha, R. S., Kitamura, D., Kurosaki, T., Ellmeier, W., Takayanagi, H. <strong>Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.</strong> Cell 132: 794-806, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18329366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18329366</a>] [<a href="https://doi.org/10.1016/j.cell.2007.12.037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18329366">Shinohara et al. (2008)</a> showed that these tyrosine kinases were crucial in Rankl (TNFSF11; <a href="/entry/602642">602642</a>)-induced osteoclastogenesis. In response to Rankl stimulation, Btk and Tec formed a signaling complex required for osteoclastogenesis with adaptor molecules such as Blnk (<a href="/entry/604515">604515</a>), which also recruited Syk (<a href="/entry/600085">600085</a>), linking Rank (TNFRSF11A; <a href="/entry/603499">603499</a>) and ITAM (see <a href="/entry/608740">608740</a>) signals to phosphorylate Plc-gamma (see <a href="/entry/172420">172420</a>). Tec kinase inhibition reduced osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. <a href="#42" class="mim-tip-reference" title="Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., Takai, T., Kodama, T., Morio, T., Geha, R. S., Kitamura, D., Kurosaki, T., Ellmeier, W., Takayanagi, H. <strong>Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.</strong> Cell 132: 794-806, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18329366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18329366</a>] [<a href="https://doi.org/10.1016/j.cell.2007.12.037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18329366">Shinohara et al. (2008)</a> concluded that their studies provided a link between immunodeficiency and abnormal bone homeostasis owing to defects in signaling molecules shared by B cells and osteoclasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18329366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Mao, L., Kitani, A., Hiejima, E., Montgomery-Recht, K., Zhou, W., Fuss, I., Wiestner, A., Strober, W. <strong>Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1-beta-mediated colitis.</strong> J. Clin. Invest. 130: 1793-1807, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31895698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31895698</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31895698[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI128322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31895698">Mao et al. (2020)</a> found that Btk -/- mice were more susceptible to experimental colitis than wildtype mice. Increased colitis in Btk -/- mice was largely due to excess Il1-beta (IL1B; <a href="/entry/147720">147720</a>) secretion arising from increased Nlpr3 inflammasome activity. Consequently, blockade of Il1-beta ameliorated increased colitis in Btk -/- mice. Treatment of wildtype mice with a Btk inhibitor revealed that, similar to in vitro studies, Btk inhibition regulated Nlrp3 inflammasome activation in vivo in a dose-dependent manner. Mice treated with low-dose inhibitor phenocopied Btk -/- mice and exhibited increased susceptibility to experimental colitis, whereas mice treated with high-dose inhibitor exhibited the opposite effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31895698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>56 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300300[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620183;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> identified a G-to-A transition at nucleotide 1706 in the BTK gene, resulting in a change of arginine-525 to glutamine. This conserved amino acid substitution was predicted to have a highly detrimental effect on the catalytic function of the putative protein-tyrosine kinase. Loss of the conserved arg525 could prevent substrate recognition because this residue is thought to be important in the substrate-specific domain. <a href="#34" class="mim-tip-reference" title="Ohta, Y., Haire, R. N., Litman, R. T., Fu, S. M., Nelson, R. P., Kratz, J., Kornfeld, S. J., de la Morena, M., Good, R. A., Litman, G. W. <strong>Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.</strong> Proc. Nat. Acad. Sci. 91: 9062-9066, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8090769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8090769</a>] [<a href="https://doi.org/10.1073/pnas.91.19.9062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8090769">Ohta et al. (1994)</a> also described the arg525-to-gln mutation in a family in which the diagnosis of common variable immunodeficiency disease had been made. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8090769+8380905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#48" class="mim-tip-reference" title="Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. <strong>The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.</strong> Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380905</a>] [<a href="https://doi.org/10.1038/361226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380905">Vetrie et al. (1993)</a> identified an A-to-G transition at position 1420 in the BTK gene, resulting in a substitution of glutamic acid for lysine-430. Substitution of lys430 (equivalent to lys295 of v-src) within the ATP-binding site would completely abolish kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8380905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935478;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012099 OR RCV003511975" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012099, RCV003511975" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012099...</a>
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<p>Like most other cytoplasmic tyrosine kinases, the Bruton tyrosine kinase contains a unique amino terminal region, SH3 and SH2 domains (short for SRC homology 3 and 2, respectively), and a carboxy-terminal kinase domain. In a patient with atypical X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#39" class="mim-tip-reference" title="Saffran, D. C., Parolini, O., Fitch-Hilgenberg, M. E., Rawlings, D. J., Afar, D. E. H., Witte, O. N., Conley, M. E. <strong>A point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia.</strong> New Eng. J. Med. 330: 1488-1491, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164701</a>] [<a href="https://doi.org/10.1056/NEJM199405263302104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164701">Saffran et al. (1994)</a> found a point mutation in the SH2 domain of BTK in a B-cell line. SH2 domains are critical mediators of binding with phosphotyrosine-containing proteins in the cell. The mutation was located in what crystal-structure studies of the SRC SH2 domain predict is a critical hydrophobic binding pocket. The consequence of this mutation is predicted to be decreased stability of the BTK protein, possibly resulting from the inability of BTK to interact with important substrates. The patient was a 23-year-old man who was the oldest of 3 brothers previously described as having atypical X-linked agammaglobulinemia by <a href="#11" class="mim-tip-reference" title="Conley, M. E., Puck, J. M. <strong>Carrier detection in typical and atypical X-linked agammaglobulinemia.</strong> J. Pediat. 112: 688-694, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2896233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2896233</a>] [<a href="https://doi.org/10.1016/s0022-3476(88)80683-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2896233">Conley and Puck (1988)</a>. A diagnosis of hypogammaglobulinemia was made when the proband was 6 years old and his brothers were 5 and 2 years old. Without therapy, the patient's serum IgG concentration was 590 mg per deciliter. All 3 brothers had 0.3 to 2% B cells in the peripheral circulation, whereas patients with typical Bruton agammaglobulinemia have a mean of 0.1% and normal subjects have 5 to 15% B cells. Although the patient complied poorly with therapy, he had not had serious infections. The single point mutation found in the SH2 domain of the coding sequence changed amino acid residue 361 from tyrosine to cysteine as a result of a TAC-to-TGC transition. <a href="#4" class="mim-tip-reference" title="Buckley, R. H. <strong>Assessing inheritance of agammaglobulinemia. (Editorial)</strong> New Eng. J. Med. 330: 1526-1528, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164707</a>] [<a href="https://doi.org/10.1056/NEJM199405263302111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164707">Buckley (1994)</a>, who provided a diagram of the structure of the BTK protein, suggested that some of the other less severe antibody-deficiency syndromes in humans could be caused by mutations in the non-kinase portions of the BTK gene. In addition, she pointed with interest to the fact that BTK is also expressed in cells of the myeloid lineage and that it is well known that intermittent neutropenia occurs in boys with X-linked agammaglobulinemia, particularly at the height of an acute infection (<a href="#3" class="mim-tip-reference" title="Buckley, R. H., Rowlands, D. T., Jr. <strong>Agammaglobulinemia, neutropenia, fever, and abdominal pain.</strong> J. Allergy Clin. Immun. 51: 308-318, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4697357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4697357</a>] [<a href="https://doi.org/10.1016/0091-6749(73)90133-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4697357">Buckley and Rowlands, 1973</a>). She raised the possibility that BTK is only one of the signaling molecules in myeloid maturation and that neutropenia may develop in X-linked agammaglobulinemia only when white cell production is rapid. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2896233+8164701+4697357+8164707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with mild X-linked agammaglobulinemia, <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified an A-to-G transition in exon 12, resulting in a substitution of cysteine for tyrosine-361. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321659 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321659;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012100" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012100" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012100</a>
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<p>In a sporadic case of the syndrome of X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; <a href="/entry/307200">307200</a>), <a href="#16" class="mim-tip-reference" title="Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. <strong>An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency.</strong> FEBS Lett. 346: 165-170, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8013627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8013627</a>] [<a href="https://doi.org/10.1016/0014-5793(94)00457-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8013627">Duriez et al. (1994)</a> analyzed the BTK gene by RT-PCR, sequencing of cDNA and genomic DNA, and in vitro splicing assays to demonstrate an intronic point mutation, 1882+5G-A, located in the tyrosine kinase domain. This exon-skipping event resulted in a frameshift leading to a premature stop codon 14 amino acids downstream and in the loss of the last 61 residues of the carboxy-terminal end of the protein. The possibility that a mutant form of BTK may give rise to XLA alone in most cases but that some mutant forms can generate both XLA and IGHD suggests that the BTK gene is expressed in the pituitary gland. To test this hypothesis, <a href="#16" class="mim-tip-reference" title="Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. <strong>An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency.</strong> FEBS Lett. 346: 165-170, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8013627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8013627</a>] [<a href="https://doi.org/10.1016/0014-5793(94)00457-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8013627">Duriez et al. (1994)</a> carried out 30 cycles of RT-PCR on mRNA from pituitaries, and the product was sequenced. This led to the detection of a specific BTK amplification product of expected size and sequence. The finding tempted <a href="#16" class="mim-tip-reference" title="Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. <strong>An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency.</strong> FEBS Lett. 346: 165-170, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8013627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8013627</a>] [<a href="https://doi.org/10.1016/0014-5793(94)00457-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8013627">Duriez et al. (1994)</a> to speculate that the protein tyrosine kinase encoded by the BTK gene plays a role in the biosynthesis or secretion of growth hormone and that some mutant forms of the BTK protein can impair both the production of growth hormone and the development of B lineage cells. They stated that 'characterisation of additional BTK gene mutations in the rare patients inheriting both XLA and IGHD is eagerly awaited.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8013627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620185 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620185;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012101 OR RCV000427660 OR RCV000583846 OR RCV000819061" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012101, RCV000427660, RCV000583846, RCV000819061" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012101...</a>
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<p><a href="#34" class="mim-tip-reference" title="Ohta, Y., Haire, R. N., Litman, R. T., Fu, S. M., Nelson, R. P., Kratz, J., Kornfeld, S. J., de la Morena, M., Good, R. A., Litman, G. W. <strong>Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.</strong> Proc. Nat. Acad. Sci. 91: 9062-9066, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8090769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8090769</a>] [<a href="https://doi.org/10.1073/pnas.91.19.9062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8090769">Ohta et al. (1994)</a> described cases of X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>) with a G-to-A transition at nucleotide 215 of the BTK gene, resulting in an arg28-to-his (R28H) amino acid replacement. The same amino acid change occurs as the cause of xid in the mouse but the mutation is a C-to-T transition at nucleotide 214. The arg28-to-his mutation was described in a case of XLA by <a href="#13" class="mim-tip-reference" title="de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. <strong>Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice.</strong> Hum. Molec. Genet. 3: 161-166, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162018</a>] [<a href="https://doi.org/10.1093/hmg/3.1.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162018">de Weers et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8090769+8162018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Wood, P. M. D., Mayne, A., Joyce, H., Smith, C. I. E., Granoff, D. M., Kumararatne, D. S. <strong>A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency.</strong> J. Pediat. 139: 148-151, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445810</a>] [<a href="https://doi.org/10.1067/mpd.2001.115970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445810">Wood et al. (2001)</a> found the R28H mutation in a 25-year-old man with a selective antipolysaccharide antibody deficiency whose IgG levels had fallen slightly below the normal range since the age of 23 years but who had remained well on antibiotic prophylaxis for 12 years. The authors suggested that male patients with antipolysaccharide antibody deficiency should be evaluated for B-cell lymphopenia and BTK mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620186 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620186;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012102 OR RCV003511976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012102, RCV003511976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012102...</a>
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<p><a href="#5" class="mim-tip-reference" title="Bykowsky, M. J., Haire, R. N., Ohta, Y., Tang, H., Sung, S.-S. J., Veksler, E. S., Greene, J. M., Fu, S. M., Litman, G. W., Sullivan, K. E. <strong>Discordant phenotype in siblings with X-linked agammaglobulinemia.</strong> Am. J. Hum. Genet. 58: 477-483, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644706</a>]" pmid="8644706">Bykowsky et al. (1996)</a> described 2 brothers with a T-to-C transition at nucleotide 134 of the BTK gene that resulted in a change of the translation initiation ATG (met) to ACG (thr). The brothers had different clinical and laboratory phenotypes. The proband lacked immunoglobulins and B cells and had recurrent infections, whereas his older affected brother had normal levels of IgG and IgM and very few infections. Both had undetectable levels of BTK kinase activity in circulating mononuclear cells. Complete sequencing of the BTK gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 HYPOGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ALA-ASP, 1952C-A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012103" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012103" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012103</a>
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<p><a href="#23" class="mim-tip-reference" title="Jones, A., Bradley, L., Alterman, L., Tarlow, M., Thompson, R., Kinnon, C., Morgan, G. <strong>X linked agammaglobulinaemia with a 'leaky' phenotype.</strong> Arch. Dis. Child. 74: 548-549, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8758136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8758136</a>] [<a href="https://doi.org/10.1136/adc.74.6.548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8758136">Jones et al. (1996)</a> described 3 brothers affected by immunodeficiency characterized by low B cell numbers and hypogammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), but normal T cell numbers and function. One brother presented at the age of 2 years with pneumococcal pneumonia and empyema requiring thoracotomy. He had a history of recurrent chest infections and severe otitis media. He developed pneumococcal meningitis at 5 years, at which time the diagnosis of hypogammaglobulinemia was first made. The second brother presented at the age of 2 years with a cervical abscess, followed several months later by an episode of pneumococcal meningitis. At 3 years he developed pneumococcal pericarditis requiring pericardiectomy. This occurred concurrently with his elder brother's pneumococcal meningitis, and as a result both boys were investigated and found to have hypogammaglobulinemia. Both boys received routine immunizations as well as Pneumovax. The third brother was identified by screening at the age of 8 weeks because of immunodeficiency in the older brothers. None of the brothers had received regular immunoglobulin replacement treatment. Analysis of cDNA prepared from the 3 affected brothers identified a single nucleotide alteration (C-to-A) at nucleotide 1952 (1952C-A) of the BTK gene. This resulted in a nonpolar-to-polar amino acid substitution (alanine to aspartic acid) in the kinase domain near the C-terminal end of the BTK protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8758136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620187;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012097 OR RCV005089231" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012097, RCV005089231" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012097...</a>
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<p>In 2 patients with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a C-to-T transition at a CpG dinucleotide in exon 2 of the BTK gene, resulting in a stop codon at position 13 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, GLN15TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620188 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620188;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012098 OR RCV001027550 OR RCV002512977" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012098, RCV001027550, RCV002512977" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012098...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a C-to-T transition at a CpG dinucleotide in exon 2 of the BTK gene, resulting in a stop codon at position 15 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0010 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, THR33PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128620189 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128620189;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128620189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128620189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012104" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012104" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012104</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 patients with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified an A-to-C transversion at position 229 of the BTK gene, resulting in a substitution of proline for threonine-33 in the pleckstrin homology domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 4-BP DEL, CODON 76, GAAA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321660 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321660;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012105 OR RCV005089232" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012105, RCV005089232" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012105...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 4-bp (GAAA) deletion at codons 76 and 77 in exon 3 of the BTK gene, resulting in a frameshift and a premature stop codon at position 120. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 2-BP DEL, IVS2DS, +3AA
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321661 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321661;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012106</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a 2-bp deletion at the 5-prime end of intron 2 of the BTK gene. Two adenines were deleted from positions +3 and +4 of the consensus sequence GTAAGT at the donor splice site. Although the deletion does not break the GT/AG boundary rule, the resulting donor splice site does not match the consensus sequence, and the mutation would most likely result in exon 2 skipping. This would remove the 5-prime end of the coding sequence, including the translation start site and the PH domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, IVS4AS, G-C, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321662 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321662;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012107 OR RCV003511977" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012107, RCV003511977" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012107...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a G-to-C transversion at the first nucleotide of the acceptor splice site of intron 4 in the BTK gene, which breaks the GT/AG exon-intron boundary rule. The skipping of exon 5 would cause a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</h4>
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BTK, 21-BP INS, NT442
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321663 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321663;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012108" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012108" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012108</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#2" class="mim-tip-reference" title="Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C. <strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong> Hum. Molec. Genet. 3: 79-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>] [<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162056">Bradley et al. (1994)</a> identified a 21-bp insertion at position 442 in the 5-prime terminal region of the BTK gene, resulting in an in-frame insertion of 7 amino acids (ser-val-phe-ser-ser-thr-arg) between amino acids 103 and 104 in the protein. <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> found that the inserted sequence matched the 3-prime acceptor sequence of intron 4 except for an A-to-G transition at position -2 from the 3-prime end. This base substitution breaks the GT/AG boundary rule. An alternative splice site 22-bp upstream of the normal 3-prime intron boundary matches the AG acceptor consensus sequence and would explain the 21-bp inserted sequence from the patient's cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7880320+8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621190 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621190;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012109</a>
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a T-to-A transversion in exon 5 of the BTK gene, resulting in a substitution of aspartic acid for valine-113 in the pleckstrin homology domain. This patient was below the fifth percentile in height, but when evaluated for growth hormone deficiency, was found to have normal growth hormone production. It is possible that other genetic or environmental factors, in concert with absent or defective Btk, cause growth hormone deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 1-BP DEL, CODON 130, A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321664 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321664;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012110 OR RCV005089233" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012110, RCV005089233" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012110...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 1-bp (A) deletion at codon 130 in exon 5 of the BTK gene, resulting in a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 1-BP INS, CODON 186, A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864321665 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321665;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864321665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864321665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012111 OR RCV000691136" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012111, RCV000691136" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012111...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 1-bp (A) insertion at codon 186 in exon 7 of the BTK gene, resulting in a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569293253 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569293253;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569293253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569293253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012112" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012112" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012112</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#13" class="mim-tip-reference" title="de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. <strong>Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice.</strong> Hum. Molec. Genet. 3: 161-166, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162018</a>] [<a href="https://doi.org/10.1093/hmg/3.1.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162018">de Weers et al. (1994)</a> identified an 8-bp (CTACATAG) insertion at position A721 in the N-terminal region of the BTK gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569292813 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569292813;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569292813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569292813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012113" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012113" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012113</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 1-bp (A) deletion at codon 218 in exon 8 of the BTK gene, resulting in a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621191 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621191;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012114</a>
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a G-to-T transversion in the BTK gene, resulting in a stop codon at position 240 and a truncated protein. This mutation was found in the SH3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0021 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, TRP252TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621192;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012115 OR RCV003511978" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012115, RCV003511978" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012115...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a G-to-A transition in exon 8 of the BTK gene, resulting in a stop codon at position 252 and a truncated protein. This mutation was found in the SH3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG255TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621193 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621193;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012116 OR RCV000583310 OR RCV001221640 OR RCV001269823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012116, RCV000583310, RCV001221640, RCV001269823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012116...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#2" class="mim-tip-reference" title="Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C. <strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong> Hum. Molec. Genet. 3: 79-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>] [<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162056">Bradley et al. (1994)</a> identified a C-to-T transition at position 895 of the BTK gene, resulting in a stop codon at position 255 and a severely truncated protein lacking the remaining 404 amino acids, which include the SH2 and kinase domains. This patient and his brother have no detectable B-cells, confirming that the absence of the functional domains of Btk results in a classic XLA phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, IVS9DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569292649 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569292649;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569292649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569292649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012117" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012117" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012117</a>
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<p>In 2 patients with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a G-to-A transition at nucleotide 909 of the BTK gene, which is the first nucleotide of the donor splice site of intron 9. The mutation causes a deletion of 21 amino acids between residues gln260 and glu280 due to skipping of exon 9. This mutation was found in the SH3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 1-BP DEL/3-BP INS, CODON 261
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012118" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012118" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012118</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 1-bp (G) deletion associated with a 3-bp (TTA) insertion at codon 261 in exon 9 of the BTK gene, resulting in a frameshift. This mutation was found in the SH3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0025" class="mim-anchor"></a>
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<strong>.0025 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG288TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621194 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621194;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012119 OR RCV000768159 OR RCV001384086 OR RCV001701564" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012119, RCV000768159, RCV001384086, RCV001701564" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012119...</a>
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#13" class="mim-tip-reference" title="de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. <strong>Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice.</strong> Hum. Molec. Genet. 3: 161-166, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162018</a>] [<a href="https://doi.org/10.1093/hmg/3.1.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162018">de Weers et al. (1994)</a> identified a C-to-T transition at position 993 of the BTK gene, resulting in a substitution of tryptophan for arginine-288. This mutation was found in the SH2-like domain where arg288 is highly conserved and crucial for the interaction with the aromatic ring of phosphotyrosine. Therefore, the replacement of arg288 by a nonpolar tryptophan would entirely abrogate the formation of the high-affinity complex with phosphotyrosine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0026 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG307GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621195 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621195;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012120</a>
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#2" class="mim-tip-reference" title="Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C. <strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong> Hum. Molec. Genet. 3: 79-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>] [<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162056">Bradley et al. (1994)</a> identified an A-to-G transition at position 1051 of the BTK gene, resulting in a substitution of glycine for arginine-307. This mutation was found in the SH2-like domain where arg307 is involved in the binding interactions at the base of the phosphotyrosine binding pocket. The change to a neutral glycine residue is highly likely to disrupt the binding potential of this region. This patient has less than 1% B cells and undetectable immunoglobulin levels, indicating that the replacement of this highly conserved arginine residue completely abolishes the functioning of Btk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0027 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, TYR334SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012121</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified an A-to-C transversion at position 1133 in exon 12 of the BTK gene, resulting in a substitution of serine for tyrosine-334. This mutation was found in the SH2-like domain where tyr334 is most likely responsible for the substrate recognition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 1-BP DEL, IVS11DS, +1G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2147430166 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147430166;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2147430166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2147430166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012122" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012122" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012122</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 1-bp (G) deletion that occurred in a run of 3 Gs in the last codon (325) of exon 11 and the first nucleotide of intron 11 in the BTK gene. This mutation was found in the SH2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0029 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, IVS12AS, A-T, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1603005659 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603005659;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1603005659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1603005659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001001214 OR RCV001869427 OR RCV002549158" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001001214, RCV001869427, RCV002549158" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001001214...</a>
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<p>In 3 patients with moderate to severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified an A-to-T transversion at nucleotide 1235, which is the second nucleotide of the acceptor splice site of intron 12, in the BTK gene. The mutation causes a deletion of 12-bp between residues 1235-1247, a frameshift at codon 372, and a stop codon at position 398. This mutation was found in the SH2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
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BTK, TYR375TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621197 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621197;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012124" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012124" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012124</a>
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<p>In a boy (patient 14) with X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; <a href="/entry/307200">307200</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a T-to-G transversion in exon 13 of the BTK gene, resulting in a tyr375-to-ter (Y375X) substitution in the SH2 domain. The mutation was associated with an absence of Btk transcript. The boy did not experience major infections and responded well to growth hormone treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0031" class="mim-anchor"></a>
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<strong>.0031 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 16-BP INS, NT1263
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2147429013 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147429013;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2147429013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2147429013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012125" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012125" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012125</a>
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<p>In 4 patients with moderate X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a 16-bp insertion (duplication) at position 1263 of the BTK cDNA, resulting in a frameshift and a premature stop codon in position 404. This mutation was found in the SH2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0032 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, LEU408PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621198 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621198;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012126" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012126" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012126</a>
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<p>In 2 patients with moderate X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a T-to-C transition at position 1355 in the BTK gene, resulting in a substitution of proline for leucine-408. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0033" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0033 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div style="float: left;">
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BTK, TYR425TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs128621199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621199;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs128621199?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012127" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012127" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012127</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#13" class="mim-tip-reference" title="de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. <strong>Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice.</strong> Hum. Molec. Genet. 3: 161-166, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162018</a>] [<a href="https://doi.org/10.1093/hmg/3.1.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162018">de Weers et al. (1994)</a> identified a C-to-A transversion at position 1407 in the BTK gene, resulting in a stop codon at position 425 and a truncated protein. This mutation was found in the ATP-binding site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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BTK, CYS502TER
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs41310709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41310709;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41310709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41310709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012128" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012128" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012128</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a C-to-A transversion at position 1638 of the BTK gene, resulting in a stop codon at position 502 and a truncated protein. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</h4>
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<div>
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BTK, CYS506ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621200 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621200;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012129 OR RCV001035091" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012129, RCV001035091" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012129...</a>
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</span>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a T-to-C transition at position 1648 in exon 15 of the BTK gene, resulting in a substitution of arginine for cysteine-506 in the middle of the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0036" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0036 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG520TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621201;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621201" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621201" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012130 OR RCV000378493 OR RCV000582314 OR RCV001061773" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012130, RCV000378493, RCV000582314, RCV001061773" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012130...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 patients with moderate to severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> and <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a C-to-T transition at position 1690 of the BTK gene, resulting in a stop codon at position 520 (in the middle of the kinase domain) and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7880320+7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621202 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621202;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012131 OR RCV000637056 OR RCV002482855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012131, RCV000637056, RCV002482855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012131...</a>
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<p>In patients with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> and <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a G-to-A transition at position 1691 in the BTK gene, resulting in a substitution of glutamine for arginine-520. Arg-520 is a highly conserved residue among all protein kinases. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7880320+7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0038 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2147425836 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147425836;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2147425836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2147425836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012132" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012132" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012132</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a 1-bp deletion (A1720) at codon 530 in exon 16, which is in the substrate specific portion of the SH1 domain in the BTK gene. This deletion results in a frameshift that generates a stop codon at nucleotide position 1796-1798 and eliminates the C-terminal portion of the catalytic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0039 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 4-BP DEL, CODON 527, GTTT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555977592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555977592;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555977592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555977592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000582912 OR RCV000637053 OR RCV001008113 OR RCV002266990" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000582912, RCV000637053, RCV001008113, RCV002266990" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000582912...</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a 4-bp (GTTT) deletion at codons 527 and 528 in exon 16 of the BTK gene, resulting in a frameshift. The patient was the mother of a boy who died suddenly of bacterial sepsis at 11 months of age. The absence of germinal follicles in lymph nodes at autopsy examination of this child suggested the diagnosis of XLA despite the lack of family history of immunodeficiency. The mother was shown to be a carrier of XLA. Analysis of X-chromosome inactivation patterns and DNA demonstrated a pattern consistent with one normal allele and one abnormal allele on SSCP analysis of exon 16. This mutation was found in the kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0040 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621203;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012134 OR RCV001810852" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012134, RCV001810852" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012134...</a>
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<p>In a boy (patient 19) with X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; <a href="/entry/307200">307200</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a T-to-C transition in exon 16 of the BTK gene, resulting in a leu542-to-pro (L542P) substitution in the kinase domain. The patient had not experienced major infections and responded well to growth hormone replacement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0041 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, IVS16DS, G-T, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569291215 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569291215;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569291215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569291215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012135" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012135" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012135</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a G-to-T transversion at codon 544, which is the first nucleotide of the donor splice site of intron 16 in the BTK gene. The mutation preserved a potential splice donor site and the GT sequence was moved 5-prime by 1 basepair. Use of this splice site would result in a frameshift and a premature stop codon. This mutation was found in the kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0042 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG562TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621204;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012136 OR RCV000581337 OR RCV000816209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012136, RCV000581337, RCV000816209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012136...</a>
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<span class="mim-text-font">
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<p>In a patient with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> and <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a C-to-T transition in exon 17 of the BTK gene, resulting in a substitution of tryptophan for arginine-562. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7849697+7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0043" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0043 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</h4>
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BTK, TYR581ARG
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621205 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621205;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012137" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012137" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012137</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a T-to-C transition in exon 17 of the BTK gene, resulting in a substitution of arginine for tyrosine-581. The wildtype tryptophan at this site is conserved in most serine/threonine kinases as well as in most tyrosine kinases. This mutation was found in the kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0044" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0044 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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BTK, GLU589GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621206;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012138" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012138" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012138</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In 3 patients with moderate X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified an A-to-G transition at position 1898 in the BTK gene, resulting in a substitution of glycine for glutamic acid-589. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0045" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0045 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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BTK, TYR591TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621207;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012139 OR RCV003511979" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012139, RCV003511979" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012139...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a C-to-A transversion in exon 17 of the BTK gene, resulting in a stop codon at position 591 and a truncated protein. This mutation was found in the kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0046" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0046 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ALA607ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621208 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621208;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012140" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012140" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012140</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In 2 patients with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#2" class="mim-tip-reference" title="Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C. <strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong> Hum. Molec. Genet. 3: 79-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>] [<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162056">Bradley et al. (1994)</a> identified a C-to-A transition at position 1952 of the BTK gene, resulting in a substitution of aspartic acid for alanine-607 near the 3-prime end of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0047" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0047 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, GLY613ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621209 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621209;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012141" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012141" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012141</a>
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<p>In 2 patients with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a G-to-A transition at position 1970 of the BTK gene, resulting in a substitution of aspartic acid for glycine-613. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0048 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, MET630LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128621210 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128621210;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128621210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128621210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012142" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012142" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012142</a>
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<p>In a patient with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> and <a href="#17" class="mim-tip-reference" title="Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. <strong>Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia.</strong> Hum. Molec. Genet. 3: 1743-1749, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7880320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7880320</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7880320">Hagemann et al. (1994)</a> identified a T-to-A transversion in exon 18 of the BTK gene, resulting in a substitution of lysine for methionine-630. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7849697+7880320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0049 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, GLU636TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128622211 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128622211;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128622211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128622211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012143</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#2" class="mim-tip-reference" title="Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C. <strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong> Hum. Molec. Genet. 3: 79-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>] [<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162056">Bradley et al. (1994)</a> identified a G-to-T transversion at nucleotide 2038 of the BTK gene, resulting in a stop codon at position 636 and a loss of the 24 terminal amino acids from the protein, including several highly conserved residues. As there are 3 affected boys in this family who have no detectable B-cells or immunoglobulin, it is likely that the last 24 amino acids of this protein are critical for its correct expression and/or function in B-cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0050" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0050 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</h4>
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BTK, 6-BP INS, NT2041
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2147423959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147423959;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2147423959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2147423959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012144</a>
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</span>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#13" class="mim-tip-reference" title="de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. <strong>Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice.</strong> Hum. Molec. Genet. 3: 161-166, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162018</a>] [<a href="https://doi.org/10.1093/hmg/3.1.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162018">de Weers et al. (1994)</a> identified a 6-bp (TTTTAG) insertion at position A2041 in the C-terminal region of the BTK gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0051 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, LEU652PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs128622212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs128622212;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs128622212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs128622212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012145" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012145" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012145</a>
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<p>In a patient with mild X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. <strong>Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.</strong> Hum. Molec. Genet. 3: 1751-1756, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849697</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849697">Conley et al. (1994)</a> identified a T-to-C transition in exon 19 of the BTK gene, resulting in a substitution of proline for leucine-652. This leucine defines the 3-prime border of the conserved kinase domain in many tyrosine kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0052 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 26-BP INS, NT2019
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012146" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012146" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012146</a>
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<p>In a patient with severe X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#58" class="mim-tip-reference" title="Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. <strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong> Hum. Molec. Genet. 3: 1899-1900, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849721">Zhu et al. (1994)</a> identified a 26-bp insertion (duplication) at position 2019 in the BTK gene, resulting in a frameshift and a premature stop codon in position 653. This mutation was found in the SH1 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0053" class="mim-anchor"></a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894770;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012147 OR RCV000485427 OR RCV005089234" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012147, RCV000485427, RCV005089234" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012147...</a>
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<p><a href="#12" class="mim-tip-reference" title="Curtis, S. K., Hebert, M. D., Saha, B. K. <strong>Twin carriers of X-linked agammaglobulinemia (XLA) due to germline mutation in the Btk gene.</strong> Am. J. Med. Genet. 90: 229-232, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10678660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10678660</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000131)90:3<229::aid-ajmg8>3.0.co;2-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10678660">Curtis et al. (2000)</a> identified a missense mutation, 1817G-C (arg562 to pro; R562P), in exon 17 of the BTK gene in cousins with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>). The same mutation was present in both mothers (twin sisters) of the cousins, identifying them as carriers. However, the mutation was absent in all other relatives including the grandmother of the cousins (mother of the twin sisters). This suggested that the mutation had originated in the germline of one of the grandparents or in the zygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10678660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0054 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 2-BP DEL, 54TG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569292818 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569292818;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569292818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569292818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012148" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012148" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012148</a>
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<p>In a patient with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>) who developed classic type I diabetes at the age of 14 years, <a href="#30" class="mim-tip-reference" title="Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., Roep, B. O. <strong>Development of type 1 diabetes despite severe hereditary B-cell deficiency.</strong> New Eng. J. Med. 345: 1036-1040, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586956</a>] [<a href="https://doi.org/10.1056/NEJMoa010465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586956">Martin et al. (2001)</a> identified a 2-bp deletion (TG) at nucleotides 54-55 in exon 8 of the BTK gene, resulting in a frameshift at codon 214 in the TH domain and a premature stop codon at position 223 in the SH3 domain of the BTK protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0055 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, IVS1DS, G-A, +5
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1131691354 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131691354;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1131691354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1131691354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012149" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012149" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012149</a>
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<p>In a Korean family with X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>), <a href="#21" class="mim-tip-reference" title="Jo, E.-K., Kanegane, H., Nonoyama, S., Tsukada, S., Lee, J.-H., Lim, K., Shong, M., Song, C.-H., Kim, H.-J., Park, J.-K., Miyawaki, T. <strong>Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase gene from seven Korean X-linked agammaglobulinemia families.</strong> J. Immun. 167: 4038-4045, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564824</a>] [<a href="https://doi.org/10.4049/jimmunol.167.7.4038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564824">Jo et al. (2001)</a> identified a point mutation in intron 1 of the BTK gene, a G-to-A transition at position +5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11564824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0056 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, 6.1-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012150</a>
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<p><a href="#22" class="mim-tip-reference" title="Jo, E.-K., Wang, Y., Kanegane, H., Futatani, T., Song, C.-H., Park, J.-K., Kim, J. S., Kim, D. S., Ahn, K.-M., Lee, S.-I., Park, H. J., Hahn, Y. S., Lee, J.-H., Miyawaki, T. <strong>Identification of mutations in the Bruton's tyrosine kinase gene, including a novel genomic rearrangements (sic) resulting in large deletion, in Korean X-linked agammaglobulinemia patients.</strong> J. Hum. Genet. 48: 322-326, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12768435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12768435</a>] [<a href="https://doi.org/10.1007/s10038-003-0032-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12768435">Jo et al. (2003)</a> identified BTK mutations in 6 patients with presumed X-linked agammaglobulinemia (XLA; <a href="/entry/300755">300755</a>) from unrelated Korean families. Of the 6 mutations, 4 were novel, including a 6.1-kb deletion including BTK exons 11-18. The large deletion, identified by long-distance PCR, revealed Alu-Alu mediated recombination that extended from an Alu sequence in intron 10 to another Alu sequence in intron 18, spanning a distance of 6.1 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12768435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Berning1980" class="mim-tip-reference" title="Berning, A. K., Eicher, E. M., Paul, W. E., Scher, I. <strong>Mapping of the X-linked immune deficiency mutation (xid) of CBA/N mice.</strong> J. Immun. 124: 1875-1877, 1980.">Berning et al. (1980)</a>; <a href="#van1986" class="mim-tip-reference" title="van der Meer, J. W. M., Mouton, R. P., Daha, M. R., Schuurman, R. K. B. <strong>Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.</strong> J. Infect. 12: 235-239, 1986.">van der Meer et al. (1986)</a>
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<a id="Berning1980" class="mim-anchor"></a>
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Berning, A. K., Eicher, E. M., Paul, W. E., Scher, I.
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<strong>Mapping of the X-linked immune deficiency mutation (xid) of CBA/N mice.</strong>
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J. Immun. 124: 1875-1877, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7365241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7365241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7365241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C.
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<strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong>
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Hum. Molec. Genet. 3: 79-83, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162056</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/3.1.79" target="_blank">Full Text</a>]
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Buckley, R. H., Rowlands, D. T., Jr.
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<strong>Agammaglobulinemia, neutropenia, fever, and abdominal pain.</strong>
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J. Allergy Clin. Immun. 51: 308-318, 1973.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4697357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4697357</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4697357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0091-6749(73)90133-4" target="_blank">Full Text</a>]
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<a id="Buckley1994" class="mim-anchor"></a>
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Buckley, R. H.
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<strong>Assessing inheritance of agammaglobulinemia. (Editorial)</strong>
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New Eng. J. Med. 330: 1526-1528, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8164707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199405263302111" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8097835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0140-6736(93)93172-w" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="55" class="mim-anchor"></a>
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<a id="Wattanasirichaigoon2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wattanasirichaigoon, D., Benjaponpitak, S., Techasaensiri, C., Kamchaisatian, W., Vichyanond, P., Janwityanujit, S., Choubtum, L., Sirinavin, S.
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|
<strong>Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations.</strong>
|
|
J. Hum. Genet. 51: 1006-1014, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951917</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10038-006-0052-y" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="56" class="mim-anchor"></a>
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<a id="Wood2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wood, P. M. D., Mayne, A., Joyce, H., Smith, C. I. E., Granoff, D. M., Kumararatne, D. S.
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<strong>A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency.</strong>
|
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J. Pediat. 139: 148-151, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1067/mpd.2001.115970" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="57" class="mim-anchor"></a>
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<a id="Yel1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yel, L., Minegishi, Y., Coustan-Smith, E., Buckley, R. H., Trubel, H., Pachman, L. M., Kitchingman, G. R., Campana, D., Rohrer, J., Conley, M. E.
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|
<strong>Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.</strong>
|
|
New Eng. J. Med. 335: 1486-1493, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8890099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8890099</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8890099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199611143352003" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="58" class="mim-anchor"></a>
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<a id="Zhu1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D.
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<strong>Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families.</strong>
|
|
Hum. Molec. Genet. 3: 1899-1900, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/3.10.1899" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 04/06/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini - updated : 10/29/2018<br>Patricia A. Hartz - updated : 2/2/2009<br>Paul J. Converse - updated : 11/21/2008<br>Cassandra L. Kniffin - updated : 10/13/2008<br>Patricia A. Hartz - updated : 5/2/2008<br>Cassandra L. Kniffin - updated : 3/21/2007<br>Paul J. Converse - updated : 4/11/2006<br>Patricia A. Hartz - updated : 3/27/2006<br>Victor A. McKusick - updated : 1/15/2004<br>Paul J. Converse - updated : 1/25/2002<br>Paul J. Converse - updated : 1/9/2002<br>Victor A. McKusick - updated : 10/30/2001<br>Deborah L. Stone - updated : 10/19/2001<br>Victor A. McKusick - updated : 3/13/2001<br>Victor A. McKusick - updated : 2/23/2000<br>Victor A. McKusick - updated : 9/23/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Victor A. McKusick - updated : 5/15/1998<br>Victor A. McKusick - updated : 6/18/1997<br>Victor A. McKusick - updated : 2/12/1997<br>Moyra Smith - updated : 8/29/1996<br>Moyra Smith - updated : 3/13/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 04/06/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/30/2018<br>carol : 10/29/2018<br>terry : 03/28/2013<br>terry : 3/28/2013<br>terry : 10/3/2012<br>wwang : 2/17/2010<br>wwang : 9/23/2009<br>alopez : 6/2/2009<br>alopez : 5/6/2009<br>mgross : 2/2/2009<br>mgross : 12/19/2008<br>mgross : 12/18/2008<br>mgross : 11/25/2008<br>terry : 11/21/2008<br>wwang : 10/23/2008<br>ckniffin : 10/13/2008<br>mgross : 5/2/2008<br>mgross : 2/21/2008<br>wwang : 4/2/2007<br>carol : 3/28/2007<br>ckniffin : 3/21/2007<br>terry : 10/11/2006<br>mgross : 5/3/2006<br>terry : 4/11/2006<br>wwang : 4/4/2006<br>terry : 3/27/2006<br>ckniffin : 10/28/2004<br>carol : 3/17/2004<br>alopez : 1/15/2004<br>terry : 1/15/2004<br>carol : 6/11/2003<br>mgross : 1/25/2002<br>mgross : 1/9/2002<br>mcapotos : 11/14/2001<br>carol : 11/9/2001<br>mcapotos : 11/7/2001<br>terry : 10/30/2001<br>carol : 10/19/2001<br>carol : 10/19/2001<br>carol : 9/27/2001<br>cwells : 3/20/2001<br>terry : 3/13/2001<br>mcapotos : 1/22/2001<br>alopez : 2/25/2000<br>terry : 2/23/2000<br>alopez : 11/15/1999<br>mgross : 10/8/1999<br>terry : 9/23/1999<br>mgross : 6/3/1999<br>mgross : 5/26/1999<br>terry : 5/14/1999<br>dkim : 12/9/1998<br>alopez : 10/14/1998<br>carol : 8/18/1998<br>terry : 8/17/1998<br>dholmes : 7/9/1998<br>carol : 7/2/1998<br>terry : 6/4/1998<br>alopez : 6/3/1998<br>terry : 5/15/1998<br>mark : 12/22/1997<br>mark : 11/21/1997<br>alopez : 7/30/1997<br>terry : 7/24/1997<br>mark : 7/8/1997<br>carol : 6/23/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>mark : 2/12/1997<br>terry : 2/6/1997<br>terry : 1/7/1997<br>jenny : 12/9/1996<br>terry : 11/18/1996<br>mark : 11/12/1996<br>mark : 11/11/1996<br>mark : 8/29/1996<br>carol : 7/6/1996<br>joanna : 3/22/1996<br>mark : 3/13/1996<br>terry : 3/13/1996<br>mark : 3/13/1996<br>mark : 3/13/1996<br>terry : 3/12/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 10/24/1995<br>terry : 8/10/1995<br>davew : 8/25/1994<br>jason : 7/15/1994<br>mimadm : 5/12/1994<br>warfield : 3/21/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 300300
|
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</span>
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</h3>
|
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
|
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|
BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
AGAMMAGLOBULINEMIA TYROSINE KINASE; ATK<br />
|
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B-CELL PROGENITOR KINASE; BPK
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: BTK</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 234533006, 65880007;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: Xq22.1
|
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : X:101,349,450-101,390,796 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
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<span class="mim-font">
|
|
Xq22.1
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Agammaglobulinemia, X-linked 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300755
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Isolated growth hormone deficiency, type III, with agammaglobulinemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
307200
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
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|
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|
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|
|
</tbody>
|
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</table>
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</div>
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
|
|
|
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|
<span class="mim-text-font">
|
|
<p>BTK is a key regulator of B-cell development (Rawlings and Witte, 1994). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Using a positional cloning strategy to identify genes within the XLA locus on the X chromosome, followed by screening a cDNA library derived from a Burkitt lymphoma cell line, Vetrie et al. (1993) isolated BTK, which they called ATK. The ORF of ATK encodes a 659-amino acid polypeptide. Two alternative initiation codons within the same ORF would result in peptide chains of 571 and 497 amino acids, respectively, if used. ATK shares a high degree of similarity with members of the SRC (190090) family of protooncogenes that encode protein-tyrosine kinases. Northern blot analysis of RNAs derived from lymphoid lineages demonstrated that the 2.6-kb ATK mRNA was expressed in a B-cell line and in B cells of 2 patients with chronic lymphocytic leukemia, but not in T cells or a T-cell line. </p><p>Desiderio (1993) compared the structure of ATK and LTK (151520) with SRC.</p><p>Tsukada et al. (1993) independently described BTK as a cytoplasmic tyrosine kinase that they termed BPK. BPK was expressed in all cells of the B lineage and in myeloid cells. Tsukada et al. (1993) concluded that BPK is not a member of the SRC family based on the following differences: (1) the kinase catalytic domain contains the sequence DLAARN, which is similar to ABL (189980), FPS (190030), and CSK (124095), but different from the SRC family (DLRAAN); (2) BPK lacks the consensus myristoylation signal (glycine at position 2 and lysine or arginine at position 7); (3) BPK lacks the equivalent of tyrosine 527 in SRC in the C-terminal domain following the kinase sequences, which is important in regulation of kinase activity; and (4) the N-terminal region of BPK is unusually long. </p>
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<strong>Gene Structure</strong>
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<p>Rohrer et al. (1994) determined the genomic organization of the BTK gene. BTK contains 19 exons and spans 37 kb. The region 5-prime to the first untranslated exon lacks TATAA or CAAT boxes, but it contains 3 retinoic acid-binding sites. </p>
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<strong>Mapping</strong>
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<p>By in situ hybridization, Vetrie et al. (1993) mapped the BTK gene to chromosome Xq21.3-q22. Oeltjen et al. (1995) concluded that the 3-prime end of the GLA gene (300644) is 9 kb from the 5-prime end of the BTK gene, and they found 2 additional genes in the region immediately 5-prime to BTK. </p>
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<strong>Gene Function</strong>
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<p>Tsukada et al. (1993) found that BPK mRNA, protein expression, and kinase activity were all reduced or absent in XLA pre-B and B cell lines. </p><p>Although evidence from the study of XLA indicated that BTK plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remained unknown, primarily because the proteins that it interacts with had not been identified until the work of Cheng et al. (1994). They showed that BTK interacted with SRC homology 3 domains of FYN (137025), LYN (165120), and HCK (142370). All of these are protein-tyrosine kinases that are activated upon stimulation of B- and T-cell receptors. These interactions were mediated by two 10-amino acid motifs in BTK. An analogous site with the same specificity was also identified in ITK (186973), the T-cell-specific homolog of BTK. The findings of Cheng et al. (1994) extended the range of interactions mediated by SRC homology 3 domains and provided an indication of a link between BTK and previously established signaling pathways in B lymphocytes. </p><p>Uckun et al. (1996) noted that a number of human diseases including immune deficiencies apparently stem from inherited or acquired deficiencies of checkpoints that regulate the rate of apoptosis in lymphoid cells. Uckun et al. (1996) reported that DT-40 lymphoma B cells rendered BTK deficient through targeted disruption of the BTK gene did not undergo radiation-induced apoptosis. They further demonstrated that the tyrosine kinase domain of BTK was necessary for triggering radiation-induced apoptosis. </p><p>Ng et al. (2004) tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients with XLA and found that XLA B cells were selected to express a unique antibody repertoire using distinct VH and D genes favoring hydrophobic reading frames normally counterselected in healthy donor B cells. Patient B cells appeared to undergo extensive secondary recombination on both IgK (see 147200) and IgL (see 147220) loci and had a slightly increased proportion of cells expressing antinuclear antibodies. Ng et al. (2004) concluded that almost half of the antibodies expressed by XLA B cells are polyreactive and that BTK is essential for removal of autoreactive B cells. </p><p>Hantschel et al. (2007) identified the BTK tyrosine kinase and TEC kinase (600583) as major binders of the tyrosine kinase inhibitor dasatinib, which is used for treatment of BCR/ABL (see 151410)-positive CML (608232). Dasatinib did not bind ITK. In a CML cell line, they determined that a thr474-to-ile (T474I) substitution in the BTK gene conferred resistance to dasatinib. They suggested that, like the structurally homologous thr315 residue in the ABL gene (see 189980.0001), the BTK thr474 residue is the gatekeeper residue critical for dasatinib binding. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The findings suggested that dasatinib may have immunosuppressive side effects. </p><p>Using ELISA, microarray analysis, RT-PCR, and flow cytometry, Hasan et al. (2007) demonstrated that Btk -/- mouse B cells responded more efficiently to CpG-DNA stimulation by producing higher levels of proinflammatory cytokines and Il27 (608273), but lower levels of the inhibitory cytokine Il10 (124092). Tlr9 (605474) protein and mRNA expression was enhanced in Btk -/- cells, especially after Tlr9 stimulation. Whereas Btk -/- and wildtype transitional stage-1 (T1) B cells failed to proliferate and died after CpG stimulation, T2 cells, expressing higher levels of Tlr9, proliferated and matured. Hasan et al. (2007) concluded that BTK regulates both TLR9 activation and expression in B lymphocytes and is necessary for inhibitory cytokine expression. </p><p>Using bone marrow-derived macrophages (BMDMs) from mice and humans with genetic BTK deficiency, Mao et al. (2020) found that BTK regulated NLRP3 (606416) inflammasome activation, but not other inflammasomes. Similarly, exposure to low concentrations of a BTK inhibitor upregulated NLRP3 inflammasome activity, whereas high concentrations of the inhibitor caused BTK-independent inhibition of NLRP3 inflammasome activity. Overexpression and knockout analyses revealed that BTK interacted with NLRP3 and regulated its phosphorylation and oligomerization, thereby modulating NLRP3 inflammasome activation. In addition, BTK downregulated NLRP3 interaction with ASC (PYCARD; 606838) and ASC assembly. BTK also inhibited NLRP3 interaction with NEK7 (606848), thereby inhibiting NEK7 phosphorylation and oligomerization. Mutation analysis showed that the PH and PTK domains of BTK interacted with the pyrin and NACHT domains of NLRP3. The PTK domain containing the BTK kinase site played a critical role in BTK inhibition of the NLRP3 inflammasome, as BTK kinase activity was required for its inhibitory function. BTK interacted with protein PP2A (PPP2CA; 176915) and upregulated PP2A phosphorylation at tyr307. Phosphorylation of PP2A temporarily inactivated PP2A and prevented it from dephosphorylating ser5 in the NLRP3 pyrin domain, leading to inhibition of the NLRP3 inflammasome. Further analysis demonstrated that the different dosage-dependent effects of BTK inhibitors on NLRP3 inflammasome activity were due to the differential effects of the inhibitors on the interaction of NLRP3 with its downstream NLRP3 inflammasome components and on the generation of NLRP3 inflammasome products. Inhibition of the NLRP3 inflammasome by high-dose BTK inhibitor was likely an off-target effect of the inhibitors on JNK (601158) activity. </p>
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<strong>Biochemical Features</strong>
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<p>Vihinen et al. (1994) used a 3-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, to interpret the structural basis for disease in 8 independent point mutations in patients with XLA. Because arg525 of BTK had been thought to substitute functionally for a critical lysine residue in protein-serine kinases, they studied the arg525-to-gln mutation and found that it abrogated the tyrosine kinase activity of BTK. All of the 8 mutations, including lys430-to-glu (300300.0002), were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues. </p><p>Mao et al. (2001) determined the x-ray crystal structure of the BTK kinase domain in its unphosphorylated state to 2.1-angstrom resolution. The structure suggested that the trans-phosphorylation of tyr551 can lead to BTK activation by triggering an exchange of hydrogen-bonded pairs from glu445/arg544 to glu445/lys430 and subsequent relocation of helix alpha-C of the N-terminal lobe. The model also indicated that mutations in the C-terminal lobe of the kinase domain, such as R562W (300300.0042), are directly or indirectly involved in peptide substrate binding. Other disease-associated mutations in this domain (e.g., E589G; 300300.0044) alter interactions with neighboring residues. </p>
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<strong>Molecular Genetics</strong>
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<p>X-linked agammaglobulinemia (XLA; 300755) is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. Using probes derived for the Southern analysis of DNA from 33 unrelated families and 150 normal X chromosomes, Vetrie et al. (1993) detected restriction pattern abnormalities in 8 families with XLA. Five of them had deletions that were shown to be entirely intragenic to BTK, confirming involvement of BTK in XLA. Two single-base missense mutations were identified in XLA patients. The failure of pre-B cells in the bone marrow of XLA males to develop into mature, circulating B cells could be the result of the product of the mutant ATK gene failing to fulfill its role in B-cell signaling. Vetrie et al. (1993) noted that inactivation of the mouse Lck gene (153390), another member of the SRC family of tyrosine kinases, results in a thymocyte differentiation defect. </p><p>Parolini et al. (1993) identified a family in which a healthy father transmitted the XLA defect to 2 of his daughters, indicating gonadal or somatic mosaicism. To assess the frequency of this phenomenon, Conley et al. (1998) evaluated 11 sisters of 7 women who were carriers of XLA and whose mutation occurred on the paternal haplotype. None of the 11 sisters were carriers of the mutations seen in their nephews. </p><p>Vorechovsky et al. (1993) pointed out that common variable immunodeficiency (CVID) is sometimes clinically and immunologically indistinguishable from XLA if it starts early in childhood and occurs sporadically in males with a decreased number of B cells. Using a cDNA clone that represented the full-length ATK (BTK) cDNA, Vorechovsky et al. (1993) did Southern blot analysis of 39 Swedish male patients diagnosed with CVID or possible CVID. One man in his late 40s, who had had recurrent respiratory infections from infancy, lacked immunoglobulins of all isotypes, and had less than 1% B cells among peripheral blood mononuclear cells, had an abnormality of the ATK gene. The abnormality was missing in his mother but had been inherited by both of his daughters. </p><p>Vorechovsky et al. (1993) failed to find the arg28-to-cys mutation, which is found in xid in mice (see ANIMAL MODEL), in 13 unrelated patients with XLA and 2 patients with XLA and growth hormone deficiency (IGHD3; 307200). They pointed to the milder phenotype of the xid mouse compared to XLA cases and suggested that if this particular mutation occurs in the human BTK gene, it might result in a milder phenotype with normal or only moderately reduced B cells and more selective immunoglobulin deficiency in boys, which may or may not increase susceptibility to infections. </p><p>Ohta et al. (1994) reported the DNA sequence of the 18 coding exons of BTK and their flanking regions. Correlations were made between the nature of mutations and the organization of the BTK gene. They found several examples of the same mutation occurring in unrelated patients, and one of these mutations occurred at the same codon that is substituted in the xid mouse. However, in xid, the mutation occurs at the first position in the conserved arginine codon, 214C-T, and results in an arg28-to-cys substitution, whereas in human cases it occurs at the second nucleotide, 215G-A, and results in an arg28-to-his amino acid change (300300.0005). The observations suggested that a limited number of deleterious changes in BTK produce clinically recognizable XLA. XLA patients have been classified in 2 general groups: those presenting at an early age with particularly severe infections and those with less severe disease in which production of immunoglobulin is sustained at low-to-normal levels well into the first decade of life. In the latter cases, an oncogenetic change may occur in which the defective tyrosine kinase no longer can sustain the B-cell population, and a progressive reduction in immunoglobulin production occurs. Ohta et al. (1994) described the arg525-to-gln mutation (300300.0001) in patients whose disorder might have been classified as common variable immunodeficiency disease. These patients had low levels of circulating B cells at an early age with mildly decreased IgM and variable IgG levels, although all were IgA deficient. </p><p>Kornfeld et al. (1995) described the case of a 16-year-old boy who had recurrent upper respiratory tract infections at 13 months of age and was diagnosed as having transient hypogammaglobulinemia of infancy on the basis of low immunoglobulin levels, normal diphtheria and tetanus antibody responses, normal anterior and posterior cervical nodes, normal tonsillar tissue, and normal numbers of B cells in the blood. IgA levels returned to normal at 15 months of age and remained within normal limits over the next 12 months, and IgG and IgM levels remained relatively unchanged. At age 10, he began receiving intravenous gammaglobulin, which resulted in cessation of infections. The clinical picture was thought to be that of common variable immunodeficiency disease. However, gene studies revealed the deletion of exon 16 of the BTK gene resulting from a splice junction defect. The patient represents an example of the extreme variation that can occur in the XLA phenotype. </p><p>Hagemann et al. (1995) described 6 mutations in the BTK gene as the cause of XLA; 5 were novel. The mutations included 2 nonsense and 2 missense mutations, a single base deletion at an intron acceptor splice site, and a 16-bp insertion. </p><p>Kobayashi et al. (1996) reported abnormalities in the BTK gene in 12 unrelated Japanese families with X-linked agammaglobulinemia. Gene rearrangement in the kinase domain was found in 2 patients by Southern blotting. Seven point mutations, 2 small deletions, and 1 small insertion were detected by SSCP analysis and sequencing. Phenotypic heterogeneity was observed in affected family members with the same mutation. The authors concluded that analyzing BTK gene alterations with SSCP is valuable for the diagnosis of XLA patients and for carrier detection; however, the correlation between gene abnormalities and clinical features remains unclear. </p><p>Among 26 unrelated patients with XLA, Vorechovsky et al. (1997) found 24 different mutations of the BTK gene. Most resulted in the premature termination of translation. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5-prime end of the gene and missense mutations in its 3-prime part, corresponding to the catalytic domain of the enzyme. </p><p>Conley et al. (1998) analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in the BTK gene were identified in 38 of 40 families with more than 1 affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in BTK were identified in 43 of 46 patients with presumed sporadic XLA. Two of the 3 remaining patients had defects in other genes required for normal B cell development, namely the mu heavy chain gene (IGHM1; 147020), as reported by Yel et al. (1996) or the lambda-5/14.1 surrogate light chain gene (IGLL1; 146770), as reported by Minegishi et al. (1998). Both of these patients were compound heterozygotes and there were no clinical features that would distinguish them from patients with typical XLA. An Epstein-Barr virus-transformed cell line from a third patient had normal BTK cDNA by SSCP, normal BTK message by Northern blot, and normal BTK protein by Western blot. Therefore, it is unlikely that this patient had XLA. Ten mutations were found in more than one family; 1 of these occurred in 3 families. Of the 83 unique mutations included in the study of Conley et al. (1998), 43 had been described previously by their laboratory, 5 had been reported by other groups, and 35 had not been previously described. </p><p>In a study of 12 Korean patients with X-linked agammaglobulinemia, Jo et al. (2001) identified 7 mutations in the BTK gene, including a point mutation in intron 1 (300300.0055). Luciferase analysis showed reduced transcriptional activity in the intron-1 mutant compared with the wildtype. EMSA and functional analysis indicated that a nuclear protein had the ability to bind to the intron-1 mutant oligonucleotides. Jo et al. (2001) proposed that several regulatory elements mediate the transcriptional regulation of BTK and that the first intron is important in BTK promoter activity. </p><p>Sakamoto et al. (2001) suggested maternal germinal mosaicism to explain the finding of 2 sibs with XLA who had a single base deletion (563C) in exon 6 of the BTK gene and whose mother had no evidence of the mutation. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient; normal cytoplasmic expression of BTK protein was found in monocytes of the mother. </p><p>Martin et al. (2001) identified a 2-bp deletion in the BTK gene (300300.0054) in a patient with X-linked agammaglobulinemia who developed classic type I diabetes (see 222100) at the age of 14 years. Autoantibodies associated with type I diabetes were undetectable, a result consistent with the diagnosis of X-linked agammaglobulinemia. The patient's HLA type was the one that is associated with the highest genetic risk of type I diabetes. The data implied that autoantibodies are not required for either the initiation or the progression of type I diabetes. Martin et al. (2001) concluded that type I diabetes can develop in the absence of both autoantibodies and B cells. This aspect of its pathogenesis places type I diabetes in marked contrast to spontaneous autoimmune diabetes in NOD mice, which has been claimed to be B cell-dependent. The findings suggested that immunotherapy directed specifically toward B cells or autoantibodies may not be effective in preventing the destruction of beta cells. </p><p>Wattanasirichaigoon et al. (2006) reported 7 different mutations in the BTK gene among 7 patients with XLA; 4 of the mutations were novel. Six patients were Thai, and 1 patient was Burmese. </p><p>About 60% of DCLRE1C (605988) and IGHM (147020) gene defects involve gross deletions, compared with about 6% of BTK gene defects. Van Zelm et al. (2008) compared gross deletion breakpoints involving DCLRE1C, IGHM, and BTK to identify mechanisms underlying these differences in gross deletion frequencies. Their analysis suggested that gross deletions involve transposable elements or large homologous regions rather than recombination motifs. Van Zelm et al. (2008) hypothesized that the transposable element content of a gene is related to its gross deletion frequency. </p><p><strong><em>Isolated Growth Hormone Deficiency III with Agammaglobulinemia</em></strong></p><p>
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Duriez et al. (1994) found an exon-skipping mutation (300300.0004) in the BTK gene in a sporadic case of X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; 307200). </p><p>In 2 patients with growth hormone deficiency and agammaglobulinemia (patients 14 and 19), previously reported by Conley et al. (1991), Conley et al. (1994) identified mutations in the BTK gene, Y375X (300300.0030) and L542P (300300.0040), respectively. </p><p><strong><em>BTK Mutation Database</em></strong></p><p>
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Vihinen et al. (1996) described a database of BTK mutations (BTKbase) listing entries from 189 unrelated families showing 148 unique molecular events. Information was included regarding the phenotype. Mutations in all 5 domains of BTK had been observed to cause XLA, the most common class of changes being missense mutations. The mutations appeared almost uniformly throughout the molecule and frequently affected CpG sites forming arginine residues. Vihinen et al. (1999) reported that BTKbase listed 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms had been found. Most mutations led to truncation of the enzyme, and about one-third of point mutations affected CpG sites. </p>
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<strong>Animal Model</strong>
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<p>Presumably the X-linked B-lymphocyte defect of mice, studied by Marshall-Clarke et al. (1979), is homologous. This defect is characteristic of the CBA-N strain of mice (Scher et al., 1975). Defective mice lack the subpopulation of B lymphocytes responsive to certain T-independent antigens of which trinitrophenylated (TNP)-Ficoll is the prototype. Their responses to T-dependent antigens may also be impaired and they are unable to respond to the hapten phosphorylcholine (PC). They lack those B cells that form colonies when cultured in vitro. </p><p>Cohen et al. (1985) isolated a cDNA probe recognizing a family of genes, called XLR, on the mouse X chromosome, at least some members of which are closely linked to the X-linked immunodeficiency (xid) trait. </p><p>Linkage studies involving 1,114 progeny backcross revealed colocalization of the xid mutation in mice with the Btk gene (Thomas et al., 1993). The xid mutation was associated in mice with a missense mutation that altered the highly conserved arginine near the N terminus of the Btk protein. Because this region of the protein lies outside any obvious kinase domain, the xid mutation may define another aspect of tyrosine kinase. Rawlings et al. (1993) likewise mapped the xid and the Btk gene to the same region and demonstrated the same missense mutation, an arg28-to-cys change. </p><p>Drabek et al. (1997) generated transgenic mice in which expression of the human BTK gene was driven by the murine class II major histocompatibility complex Ea gene locus control region, which provides gene expression from the pre-B cell stage onwards. When these transgenic mice were mated onto a Btk(-) background, correction of the xid B cell defects was observed: B cells differentiated to mature low IgM/high IgD stages, peritoneal CD5(+) B cells were present, and serum immunoglobulin levels and in vivo responses to antigens were in the normal ranges. A comparable rescue by transgenic Btk expression was also observed in heterozygous Btk +/- female mice in those B-lineage cells that were Btk-deficient as a result of X-chromosome inactivation. </p><p>Kawakami et al. (2006) found that dendritic cells of Btk-null mice exhibited a more mature phenotype and a stronger in vitro and in vivo T cell-stimulatory ability than wildtype cells. Increased IgE responses were induced by adoptive transfer of Btk-null dendritic cells into wildtype mice. Consistent with the stronger T cell-stimulatory ability of Btk-null dendritic cells, Btk-null mice exhibited enhanced inflammation in T helper cell 2-driven asthma and T helper cell 1-driven contact sensitivity experiments. The negative regulatory functions of Btk in dendritic cells appeared to be mediated mainly through autocrine secretion of IL10 (124092) and subsequent activation of Stat3 (102582). </p><p>Using Tec (600583) -/- Btk -/- double-knockout mice, Shinohara et al. (2008) showed that these tyrosine kinases were crucial in Rankl (TNFSF11; 602642)-induced osteoclastogenesis. In response to Rankl stimulation, Btk and Tec formed a signaling complex required for osteoclastogenesis with adaptor molecules such as Blnk (604515), which also recruited Syk (600085), linking Rank (TNFRSF11A; 603499) and ITAM (see 608740) signals to phosphorylate Plc-gamma (see 172420). Tec kinase inhibition reduced osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Shinohara et al. (2008) concluded that their studies provided a link between immunodeficiency and abnormal bone homeostasis owing to defects in signaling molecules shared by B cells and osteoclasts. </p><p>Mao et al. (2020) found that Btk -/- mice were more susceptible to experimental colitis than wildtype mice. Increased colitis in Btk -/- mice was largely due to excess Il1-beta (IL1B; 147720) secretion arising from increased Nlpr3 inflammasome activity. Consequently, blockade of Il1-beta ameliorated increased colitis in Btk -/- mice. Treatment of wildtype mice with a Btk inhibitor revealed that, similar to in vitro studies, Btk inhibition regulated Nlrp3 inflammasome activation in vivo in a dose-dependent manner. Mice treated with low-dose inhibitor phenocopied Btk -/- mice and exhibited increased susceptibility to experimental colitis, whereas mice treated with high-dose inhibitor exhibited the opposite effects. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>56 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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BTK, ARG525GLN
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SNP: rs128620183,
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ClinVar: RCV000012095, RCV000581245, RCV001204367, RCV001267912
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<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Vetrie et al. (1993) identified a G-to-A transition at nucleotide 1706 in the BTK gene, resulting in a change of arginine-525 to glutamine. This conserved amino acid substitution was predicted to have a highly detrimental effect on the catalytic function of the putative protein-tyrosine kinase. Loss of the conserved arg525 could prevent substrate recognition because this residue is thought to be important in the substrate-specific domain. Ohta et al. (1994) also described the arg525-to-gln mutation in a family in which the diagnosis of common variable immunodeficiency disease had been made. </p>
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<span class="mim-font">
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<strong>.0002 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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<span class="mim-text-font">
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BTK, LYS430GLU
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<br />
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SNP: rs128620184,
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|
|
ClinVar: RCV000012096
|
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Vetrie et al. (1993) identified an A-to-G transition at position 1420 in the BTK gene, resulting in a substitution of glutamic acid for lysine-430. Substitution of lys430 (equivalent to lys295 of v-src) within the ATP-binding site would completely abolish kinase activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 AGAMMAGLOBULINEMIA, X-LINKED</strong>
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</span>
|
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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|
BTK, TYR361CYS
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<br />
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|
|
SNP: rs28935478,
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ClinVar: RCV000012099, RCV003511975
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>Like most other cytoplasmic tyrosine kinases, the Bruton tyrosine kinase contains a unique amino terminal region, SH3 and SH2 domains (short for SRC homology 3 and 2, respectively), and a carboxy-terminal kinase domain. In a patient with atypical X-linked agammaglobulinemia (XLA; 300755), Saffran et al. (1994) found a point mutation in the SH2 domain of BTK in a B-cell line. SH2 domains are critical mediators of binding with phosphotyrosine-containing proteins in the cell. The mutation was located in what crystal-structure studies of the SRC SH2 domain predict is a critical hydrophobic binding pocket. The consequence of this mutation is predicted to be decreased stability of the BTK protein, possibly resulting from the inability of BTK to interact with important substrates. The patient was a 23-year-old man who was the oldest of 3 brothers previously described as having atypical X-linked agammaglobulinemia by Conley and Puck (1988). A diagnosis of hypogammaglobulinemia was made when the proband was 6 years old and his brothers were 5 and 2 years old. Without therapy, the patient's serum IgG concentration was 590 mg per deciliter. All 3 brothers had 0.3 to 2% B cells in the peripheral circulation, whereas patients with typical Bruton agammaglobulinemia have a mean of 0.1% and normal subjects have 5 to 15% B cells. Although the patient complied poorly with therapy, he had not had serious infections. The single point mutation found in the SH2 domain of the coding sequence changed amino acid residue 361 from tyrosine to cysteine as a result of a TAC-to-TGC transition. Buckley (1994), who provided a diagram of the structure of the BTK protein, suggested that some of the other less severe antibody-deficiency syndromes in humans could be caused by mutations in the non-kinase portions of the BTK gene. In addition, she pointed with interest to the fact that BTK is also expressed in cells of the myeloid lineage and that it is well known that intermittent neutropenia occurs in boys with X-linked agammaglobulinemia, particularly at the height of an acute infection (Buckley and Rowlands, 1973). She raised the possibility that BTK is only one of the signaling molecules in myeloid maturation and that neutropenia may develop in X-linked agammaglobulinemia only when white cell production is rapid. </p><p>In a patient with mild X-linked agammaglobulinemia, Conley et al. (1994) identified an A-to-G transition in exon 12, resulting in a substitution of cysteine for tyrosine-361. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
BTK, IVS17DS, G-A, +5
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<br />
|
|
|
|
SNP: rs864321659,
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|
|
ClinVar: RCV000012100
|
|
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|
|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a sporadic case of the syndrome of X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; 307200), Duriez et al. (1994) analyzed the BTK gene by RT-PCR, sequencing of cDNA and genomic DNA, and in vitro splicing assays to demonstrate an intronic point mutation, 1882+5G-A, located in the tyrosine kinase domain. This exon-skipping event resulted in a frameshift leading to a premature stop codon 14 amino acids downstream and in the loss of the last 61 residues of the carboxy-terminal end of the protein. The possibility that a mutant form of BTK may give rise to XLA alone in most cases but that some mutant forms can generate both XLA and IGHD suggests that the BTK gene is expressed in the pituitary gland. To test this hypothesis, Duriez et al. (1994) carried out 30 cycles of RT-PCR on mRNA from pituitaries, and the product was sequenced. This led to the detection of a specific BTK amplification product of expected size and sequence. The finding tempted Duriez et al. (1994) to speculate that the protein tyrosine kinase encoded by the BTK gene plays a role in the biosynthesis or secretion of growth hormone and that some mutant forms of the BTK protein can impair both the production of growth hormone and the development of B lineage cells. They stated that 'characterisation of additional BTK gene mutations in the rare patients inheriting both XLA and IGHD is eagerly awaited.' </p>
|
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</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
BTK, ARG28HIS
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<br />
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|
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SNP: rs128620185,
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|
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|
|
|
|
ClinVar: RCV000012101, RCV000427660, RCV000583846, RCV000819061
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
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|
<span class="mim-text-font">
|
|
<p>Ohta et al. (1994) described cases of X-linked agammaglobulinemia (XLA; 300755) with a G-to-A transition at nucleotide 215 of the BTK gene, resulting in an arg28-to-his (R28H) amino acid replacement. The same amino acid change occurs as the cause of xid in the mouse but the mutation is a C-to-T transition at nucleotide 214. The arg28-to-his mutation was described in a case of XLA by de Weers et al. (1994). </p><p>Wood et al. (2001) found the R28H mutation in a 25-year-old man with a selective antipolysaccharide antibody deficiency whose IgG levels had fallen slightly below the normal range since the age of 23 years but who had remained well on antibiotic prophylaxis for 12 years. The authors suggested that male patients with antipolysaccharide antibody deficiency should be evaluated for B-cell lymphopenia and BTK mutations. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, MET1THR
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<br />
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|
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SNP: rs128620186,
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|
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|
|
ClinVar: RCV000012102, RCV003511976
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bykowsky et al. (1996) described 2 brothers with a T-to-C transition at nucleotide 134 of the BTK gene that resulted in a change of the translation initiation ATG (met) to ACG (thr). The brothers had different clinical and laboratory phenotypes. The proband lacked immunoglobulins and B cells and had recurrent infections, whereas his older affected brother had normal levels of IgG and IgM and very few infections. Both had undetectable levels of BTK kinase activity in circulating mononuclear cells. Complete sequencing of the BTK gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ALA-ASP, 1952C-A
|
|
|
|
|
|
<br />
|
|
|
|
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|
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ClinVar: RCV000012103
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Jones et al. (1996) described 3 brothers affected by immunodeficiency characterized by low B cell numbers and hypogammaglobulinemia (XLA; 300755), but normal T cell numbers and function. One brother presented at the age of 2 years with pneumococcal pneumonia and empyema requiring thoracotomy. He had a history of recurrent chest infections and severe otitis media. He developed pneumococcal meningitis at 5 years, at which time the diagnosis of hypogammaglobulinemia was first made. The second brother presented at the age of 2 years with a cervical abscess, followed several months later by an episode of pneumococcal meningitis. At 3 years he developed pneumococcal pericarditis requiring pericardiectomy. This occurred concurrently with his elder brother's pneumococcal meningitis, and as a result both boys were investigated and found to have hypogammaglobulinemia. Both boys received routine immunizations as well as Pneumovax. The third brother was identified by screening at the age of 8 weeks because of immunodeficiency in the older brothers. None of the brothers had received regular immunoglobulin replacement treatment. Analysis of cDNA prepared from the 3 affected brothers identified a single nucleotide alteration (C-to-A) at nucleotide 1952 (1952C-A) of the BTK gene. This resulted in a nonpolar-to-polar amino acid substitution (alanine to aspartic acid) in the kinase domain near the C-terminal end of the BTK protein. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG13TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128620187,
|
|
|
|
|
|
|
|
ClinVar: RCV000012097, RCV005089231
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a C-to-T transition at a CpG dinucleotide in exon 2 of the BTK gene, resulting in a stop codon at position 13 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, GLN15TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128620188,
|
|
|
|
|
|
|
|
ClinVar: RCV000012098, RCV001027550, RCV002512977
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a C-to-T transition at a CpG dinucleotide in exon 2 of the BTK gene, resulting in a stop codon at position 15 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, THR33PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128620189,
|
|
|
|
|
|
|
|
ClinVar: RCV000012104
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified an A-to-C transversion at position 229 of the BTK gene, resulting in a substitution of proline for threonine-33 in the pleckstrin homology domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 4-BP DEL, CODON 76, GAAA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864321660,
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|
|
|
|
|
|
|
ClinVar: RCV000012105, RCV005089232
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 4-bp (GAAA) deletion at codons 76 and 77 in exon 3 of the BTK gene, resulting in a frameshift and a premature stop codon at position 120. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 2-BP DEL, IVS2DS, +3AA
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs864321661,
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|
|
|
|
|
ClinVar: RCV000012106
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Hagemann et al. (1994) identified a 2-bp deletion at the 5-prime end of intron 2 of the BTK gene. Two adenines were deleted from positions +3 and +4 of the consensus sequence GTAAGT at the donor splice site. Although the deletion does not break the GT/AG boundary rule, the resulting donor splice site does not match the consensus sequence, and the mutation would most likely result in exon 2 skipping. This would remove the 5-prime end of the coding sequence, including the translation start site and the PH domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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</div>
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, IVS4AS, G-C, -1
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs864321662,
|
|
|
|
|
|
|
|
ClinVar: RCV000012107, RCV003511977
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Hagemann et al. (1994) identified a G-to-C transversion at the first nucleotide of the acceptor splice site of intron 4 in the BTK gene, which breaks the GT/AG exon-intron boundary rule. The skipping of exon 5 would cause a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 21-BP INS, NT442
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864321663,
|
|
|
|
|
|
|
|
ClinVar: RCV000012108
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a 21-bp insertion at position 442 in the 5-prime terminal region of the BTK gene, resulting in an in-frame insertion of 7 amino acids (ser-val-phe-ser-ser-thr-arg) between amino acids 103 and 104 in the protein. Hagemann et al. (1994) found that the inserted sequence matched the 3-prime acceptor sequence of intron 4 except for an A-to-G transition at position -2 from the 3-prime end. This base substitution breaks the GT/AG boundary rule. An alternative splice site 22-bp upstream of the normal 3-prime intron boundary matches the AG acceptor consensus sequence and would explain the 21-bp inserted sequence from the patient's cDNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, VAL113ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621190,
|
|
|
|
|
|
|
|
ClinVar: RCV000012109
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a T-to-A transversion in exon 5 of the BTK gene, resulting in a substitution of aspartic acid for valine-113 in the pleckstrin homology domain. This patient was below the fifth percentile in height, but when evaluated for growth hormone deficiency, was found to have normal growth hormone production. It is possible that other genetic or environmental factors, in concert with absent or defective Btk, cause growth hormone deficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP DEL, CODON 130, A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864321664,
|
|
|
|
|
|
|
|
ClinVar: RCV000012110, RCV005089233
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 1-bp (A) deletion at codon 130 in exon 5 of the BTK gene, resulting in a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP INS, CODON 186, A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864321665,
|
|
|
|
|
|
|
|
ClinVar: RCV000012111, RCV000691136
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 1-bp (A) insertion at codon 186 in exon 7 of the BTK gene, resulting in a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 8-BP INS, NT721
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569293253,
|
|
|
|
|
|
|
|
ClinVar: RCV000012112
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), de Weers et al. (1994) identified an 8-bp (CTACATAG) insertion at position A721 in the N-terminal region of the BTK gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP DEL, CODON 218, A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569292813,
|
|
|
|
|
|
|
|
ClinVar: RCV000012113
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 1-bp (A) deletion at codon 218 in exon 8 of the BTK gene, resulting in a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, GLU240TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621191,
|
|
|
|
|
|
|
|
ClinVar: RCV000012114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a G-to-T transversion in the BTK gene, resulting in a stop codon at position 240 and a truncated protein. This mutation was found in the SH3 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TRP252TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621192,
|
|
|
|
|
|
|
|
ClinVar: RCV000012115, RCV003511978
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a G-to-A transition in exon 8 of the BTK gene, resulting in a stop codon at position 252 and a truncated protein. This mutation was found in the SH3 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG255TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621193,
|
|
|
|
|
|
|
|
ClinVar: RCV000012116, RCV000583310, RCV001221640, RCV001269823
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a C-to-T transition at position 895 of the BTK gene, resulting in a stop codon at position 255 and a severely truncated protein lacking the remaining 404 amino acids, which include the SH2 and kinase domains. This patient and his brother have no detectable B-cells, confirming that the absence of the functional domains of Btk results in a classic XLA phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, IVS9DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569292649,
|
|
|
|
|
|
|
|
ClinVar: RCV000012117
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a G-to-A transition at nucleotide 909 of the BTK gene, which is the first nucleotide of the donor splice site of intron 9. The mutation causes a deletion of 21 amino acids between residues gln260 and glu280 due to skipping of exon 9. This mutation was found in the SH3 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP DEL/3-BP INS, CODON 261
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000012118
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 1-bp (G) deletion associated with a 3-bp (TTA) insertion at codon 261 in exon 9 of the BTK gene, resulting in a frameshift. This mutation was found in the SH3 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG288TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621194,
|
|
|
|
|
|
|
|
ClinVar: RCV000012119, RCV000768159, RCV001384086, RCV001701564
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), de Weers et al. (1994) identified a C-to-T transition at position 993 of the BTK gene, resulting in a substitution of tryptophan for arginine-288. This mutation was found in the SH2-like domain where arg288 is highly conserved and crucial for the interaction with the aromatic ring of phosphotyrosine. Therefore, the replacement of arg288 by a nonpolar tryptophan would entirely abrogate the formation of the high-affinity complex with phosphotyrosine. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG307GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621195,
|
|
|
|
|
|
|
|
ClinVar: RCV000012120
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified an A-to-G transition at position 1051 of the BTK gene, resulting in a substitution of glycine for arginine-307. This mutation was found in the SH2-like domain where arg307 is involved in the binding interactions at the base of the phosphotyrosine binding pocket. The change to a neutral glycine residue is highly likely to disrupt the binding potential of this region. This patient has less than 1% B cells and undetectable immunoglobulin levels, indicating that the replacement of this highly conserved arginine residue completely abolishes the functioning of Btk. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TYR334SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621196,
|
|
|
|
|
|
|
|
ClinVar: RCV000012121
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Hagemann et al. (1994) identified an A-to-C transversion at position 1133 in exon 12 of the BTK gene, resulting in a substitution of serine for tyrosine-334. This mutation was found in the SH2-like domain where tyr334 is most likely responsible for the substrate recognition. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP DEL, IVS11DS, +1G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147430166,
|
|
|
|
|
|
|
|
ClinVar: RCV000012122
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 1-bp (G) deletion that occurred in a run of 3 Gs in the last codon (325) of exon 11 and the first nucleotide of intron 11 in the BTK gene. This mutation was found in the SH2 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, IVS12AS, A-T, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603005659,
|
|
|
|
|
|
|
|
ClinVar: RCV001001214, RCV001869427, RCV002549158
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients with moderate to severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified an A-to-T transversion at nucleotide 1235, which is the second nucleotide of the acceptor splice site of intron 12, in the BTK gene. The mutation causes a deletion of 12-bp between residues 1235-1247, a frameshift at codon 372, and a stop codon at position 398. This mutation was found in the SH2 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TYR375TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621197,
|
|
|
|
|
|
|
|
ClinVar: RCV000012124
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy (patient 14) with X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; 307200), Conley et al. (1994) identified a T-to-G transversion in exon 13 of the BTK gene, resulting in a tyr375-to-ter (Y375X) substitution in the SH2 domain. The mutation was associated with an absence of Btk transcript. The boy did not experience major infections and responded well to growth hormone treatment. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 16-BP INS, NT1263
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147429013,
|
|
|
|
|
|
|
|
ClinVar: RCV000012125
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 patients with moderate X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a 16-bp insertion (duplication) at position 1263 of the BTK cDNA, resulting in a frameshift and a premature stop codon in position 404. This mutation was found in the SH2 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, LEU408PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621198,
|
|
|
|
|
|
|
|
ClinVar: RCV000012126
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with moderate X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a T-to-C transition at position 1355 in the BTK gene, resulting in a substitution of proline for leucine-408. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TYR425TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621199,
|
|
|
|
|
|
gnomAD: rs128621199,
|
|
|
|
|
|
ClinVar: RCV000012127
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), de Weers et al. (1994) identified a C-to-A transversion at position 1407 in the BTK gene, resulting in a stop codon at position 425 and a truncated protein. This mutation was found in the ATP-binding site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, CYS502TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41310709,
|
|
|
|
|
|
|
|
ClinVar: RCV000012128
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a C-to-A transversion at position 1638 of the BTK gene, resulting in a stop codon at position 502 and a truncated protein. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, CYS506ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621200,
|
|
|
|
|
|
|
|
ClinVar: RCV000012129, RCV001035091
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Hagemann et al. (1994) identified a T-to-C transition at position 1648 in exon 15 of the BTK gene, resulting in a substitution of arginine for cysteine-506 in the middle of the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG520TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621201,
|
|
|
|
|
|
|
|
ClinVar: RCV000012130, RCV000378493, RCV000582314, RCV001061773
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with moderate to severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) and Hagemann et al. (1994) identified a C-to-T transition at position 1690 of the BTK gene, resulting in a stop codon at position 520 (in the middle of the kinase domain) and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG520GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621202,
|
|
|
|
|
|
|
|
ClinVar: RCV000012131, RCV000637056, RCV002482855
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) and Hagemann et al. (1994) identified a G-to-A transition at position 1691 in the BTK gene, resulting in a substitution of glutamine for arginine-520. Arg-520 is a highly conserved residue among all protein kinases. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 1-BP DEL, 1720A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147425836,
|
|
|
|
|
|
|
|
ClinVar: RCV000012132
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Hagemann et al. (1994) identified a 1-bp deletion (A1720) at codon 530 in exon 16, which is in the substrate specific portion of the SH1 domain in the BTK gene. This deletion results in a frameshift that generates a stop codon at nucleotide position 1796-1798 and eliminates the C-terminal portion of the catalytic domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 4-BP DEL, CODON 527, GTTT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555977592,
|
|
|
|
|
|
|
|
ClinVar: RCV000582912, RCV000637053, RCV001008113, RCV002266990
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a 4-bp (GTTT) deletion at codons 527 and 528 in exon 16 of the BTK gene, resulting in a frameshift. The patient was the mother of a boy who died suddenly of bacterial sepsis at 11 months of age. The absence of germinal follicles in lymph nodes at autopsy examination of this child suggested the diagnosis of XLA despite the lack of family history of immunodeficiency. The mother was shown to be a carrier of XLA. Analysis of X-chromosome inactivation patterns and DNA demonstrated a pattern consistent with one normal allele and one abnormal allele on SSCP analysis of exon 16. This mutation was found in the kinase domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III, WITH AGAMMAGLOBULINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, LEU542PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621203,
|
|
|
|
|
|
|
|
ClinVar: RCV000012134, RCV001810852
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy (patient 19) with X-linked agammaglobulinemia and isolated growth hormone deficiency (IGHD3; 307200), Conley et al. (1994) identified a T-to-C transition in exon 16 of the BTK gene, resulting in a leu542-to-pro (L542P) substitution in the kinase domain. The patient had not experienced major infections and responded well to growth hormone replacement. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, IVS16DS, G-T, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569291215,
|
|
|
|
|
|
|
|
ClinVar: RCV000012135
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a G-to-T transversion at codon 544, which is the first nucleotide of the donor splice site of intron 16 in the BTK gene. The mutation preserved a potential splice donor site and the GT sequence was moved 5-prime by 1 basepair. Use of this splice site would result in a frameshift and a premature stop codon. This mutation was found in the kinase domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG562TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621204,
|
|
|
|
|
|
|
|
ClinVar: RCV000012136, RCV000581337, RCV000816209
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mild X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) and Hagemann et al. (1994) identified a C-to-T transition in exon 17 of the BTK gene, resulting in a substitution of tryptophan for arginine-562. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TYR581ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621205,
|
|
|
|
|
|
|
|
ClinVar: RCV000012137
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mild X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a T-to-C transition in exon 17 of the BTK gene, resulting in a substitution of arginine for tyrosine-581. The wildtype tryptophan at this site is conserved in most serine/threonine kinases as well as in most tyrosine kinases. This mutation was found in the kinase domain. </p>
|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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|
|
<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, GLU589GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621206,
|
|
|
|
|
|
|
|
ClinVar: RCV000012138
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients with moderate X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified an A-to-G transition at position 1898 in the BTK gene, resulting in a substitution of glycine for glutamic acid-589. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, TYR591TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs128621207,
|
|
|
|
|
|
|
|
ClinVar: RCV000012139, RCV003511979
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a C-to-A transversion in exon 17 of the BTK gene, resulting in a stop codon at position 591 and a truncated protein. This mutation was found in the kinase domain. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ALA607ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621208,
|
|
|
|
|
|
|
|
ClinVar: RCV000012140
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with mild X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a C-to-A transition at position 1952 of the BTK gene, resulting in a substitution of aspartic acid for alanine-607 near the 3-prime end of the gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0047 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, GLY613ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621209,
|
|
|
|
|
|
|
|
ClinVar: RCV000012141
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with mild X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a G-to-A transition at position 1970 of the BTK gene, resulting in a substitution of aspartic acid for glycine-613. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0048 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, MET630LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128621210,
|
|
|
|
|
|
|
|
ClinVar: RCV000012142
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mild X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) and Hagemann et al. (1994) identified a T-to-A transversion in exon 18 of the BTK gene, resulting in a substitution of lysine for methionine-630. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0049 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, GLU636TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128622211,
|
|
|
|
|
|
|
|
ClinVar: RCV000012143
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), Bradley et al. (1994) identified a G-to-T transversion at nucleotide 2038 of the BTK gene, resulting in a stop codon at position 636 and a loss of the 24 terminal amino acids from the protein, including several highly conserved residues. As there are 3 affected boys in this family who have no detectable B-cells or immunoglobulin, it is likely that the last 24 amino acids of this protein are critical for its correct expression and/or function in B-cell development. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0050 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 6-BP INS, NT2041
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147423959,
|
|
|
|
|
|
|
|
ClinVar: RCV000012144
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755), de Weers et al. (1994) identified a 6-bp (TTTTAG) insertion at position A2041 in the C-terminal region of the BTK gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0051 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, LEU652PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs128622212,
|
|
|
|
|
|
|
|
ClinVar: RCV000012145
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mild X-linked agammaglobulinemia (XLA; 300755), Conley et al. (1994) identified a T-to-C transition in exon 19 of the BTK gene, resulting in a substitution of proline for leucine-652. This leucine defines the 3-prime border of the conserved kinase domain in many tyrosine kinases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0052 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 26-BP INS, NT2019
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000012146
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe X-linked agammaglobulinemia (XLA; 300755), Zhu et al. (1994) identified a 26-bp insertion (duplication) at position 2019 in the BTK gene, resulting in a frameshift and a premature stop codon in position 653. This mutation was found in the SH1 domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0053 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, ARG562PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894770,
|
|
|
|
|
|
|
|
ClinVar: RCV000012147, RCV000485427, RCV005089234
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Curtis et al. (2000) identified a missense mutation, 1817G-C (arg562 to pro; R562P), in exon 17 of the BTK gene in cousins with X-linked agammaglobulinemia (XLA; 300755). The same mutation was present in both mothers (twin sisters) of the cousins, identifying them as carriers. However, the mutation was absent in all other relatives including the grandmother of the cousins (mother of the twin sisters). This suggested that the mutation had originated in the germline of one of the grandparents or in the zygote. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0054 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 2-BP DEL, 54TG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569292818,
|
|
|
|
|
|
|
|
ClinVar: RCV000012148
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with X-linked agammaglobulinemia (XLA; 300755) who developed classic type I diabetes at the age of 14 years, Martin et al. (2001) identified a 2-bp deletion (TG) at nucleotides 54-55 in exon 8 of the BTK gene, resulting in a frameshift at codon 214 in the TH domain and a premature stop codon at position 223 in the SH3 domain of the BTK protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0055 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, IVS1DS, G-A, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1131691354,
|
|
|
|
|
|
|
|
ClinVar: RCV000012149
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Korean family with X-linked agammaglobulinemia (XLA; 300755), Jo et al. (2001) identified a point mutation in intron 1 of the BTK gene, a G-to-A transition at position +5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0056 AGAMMAGLOBULINEMIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BTK, 6.1-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000012150
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Jo et al. (2003) identified BTK mutations in 6 patients with presumed X-linked agammaglobulinemia (XLA; 300755) from unrelated Korean families. Of the 6 mutations, 4 were novel, including a 6.1-kb deletion including BTK exons 11-18. The large deletion, identified by long-distance PCR, revealed Alu-Alu mediated recombination that extended from an Alu sequence in intron 10 to another Alu sequence in intron 18, spanning a distance of 6.1 kb. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Berning et al. (1980); van der Meer et al. (1986)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Berning, A. K., Eicher, E. M., Paul, W. E., Scher, I.
|
|
<strong>Mapping of the X-linked immune deficiency mutation (xid) of CBA/N mice.</strong>
|
|
J. Immun. 124: 1875-1877, 1980.
|
|
|
|
|
|
[PubMed: 7365241]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. J., Kinnon, C.
|
|
<strong>Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis.</strong>
|
|
Hum. Molec. Genet. 3: 79-83, 1994.
|
|
|
|
|
|
[PubMed: 8162056]
|
|
|
|
|
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Contributors:
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Bao Lige - updated : 04/06/2022<br>Carol A. Bocchini - updated : 10/29/2018<br>Patricia A. Hartz - updated : 2/2/2009<br>Paul J. Converse - updated : 11/21/2008<br>Cassandra L. Kniffin - updated : 10/13/2008<br>Patricia A. Hartz - updated : 5/2/2008<br>Cassandra L. Kniffin - updated : 3/21/2007<br>Paul J. Converse - updated : 4/11/2006<br>Patricia A. Hartz - updated : 3/27/2006<br>Victor A. McKusick - updated : 1/15/2004<br>Paul J. Converse - updated : 1/25/2002<br>Paul J. Converse - updated : 1/9/2002<br>Victor A. McKusick - updated : 10/30/2001<br>Deborah L. Stone - updated : 10/19/2001<br>Victor A. McKusick - updated : 3/13/2001<br>Victor A. McKusick - updated : 2/23/2000<br>Victor A. McKusick - updated : 9/23/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Victor A. McKusick - updated : 5/15/1998<br>Victor A. McKusick - updated : 6/18/1997<br>Victor A. McKusick - updated : 2/12/1997<br>Moyra Smith - updated : 8/29/1996<br>Moyra Smith - updated : 3/13/1996
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Victor A. McKusick : 6/4/1986
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mgross : 04/06/2022<br>carol : 10/30/2018<br>carol : 10/29/2018<br>terry : 03/28/2013<br>terry : 3/28/2013<br>terry : 10/3/2012<br>wwang : 2/17/2010<br>wwang : 9/23/2009<br>alopez : 6/2/2009<br>alopez : 5/6/2009<br>mgross : 2/2/2009<br>mgross : 12/19/2008<br>mgross : 12/18/2008<br>mgross : 11/25/2008<br>terry : 11/21/2008<br>wwang : 10/23/2008<br>ckniffin : 10/13/2008<br>mgross : 5/2/2008<br>mgross : 2/21/2008<br>wwang : 4/2/2007<br>carol : 3/28/2007<br>ckniffin : 3/21/2007<br>terry : 10/11/2006<br>mgross : 5/3/2006<br>terry : 4/11/2006<br>wwang : 4/4/2006<br>terry : 3/27/2006<br>ckniffin : 10/28/2004<br>carol : 3/17/2004<br>alopez : 1/15/2004<br>terry : 1/15/2004<br>carol : 6/11/2003<br>mgross : 1/25/2002<br>mgross : 1/9/2002<br>mcapotos : 11/14/2001<br>carol : 11/9/2001<br>mcapotos : 11/7/2001<br>terry : 10/30/2001<br>carol : 10/19/2001<br>carol : 10/19/2001<br>carol : 9/27/2001<br>cwells : 3/20/2001<br>terry : 3/13/2001<br>mcapotos : 1/22/2001<br>alopez : 2/25/2000<br>terry : 2/23/2000<br>alopez : 11/15/1999<br>mgross : 10/8/1999<br>terry : 9/23/1999<br>mgross : 6/3/1999<br>mgross : 5/26/1999<br>terry : 5/14/1999<br>dkim : 12/9/1998<br>alopez : 10/14/1998<br>carol : 8/18/1998<br>terry : 8/17/1998<br>dholmes : 7/9/1998<br>carol : 7/2/1998<br>terry : 6/4/1998<br>alopez : 6/3/1998<br>terry : 5/15/1998<br>mark : 12/22/1997<br>mark : 11/21/1997<br>alopez : 7/30/1997<br>terry : 7/24/1997<br>mark : 7/8/1997<br>carol : 6/23/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>mark : 2/12/1997<br>terry : 2/6/1997<br>terry : 1/7/1997<br>jenny : 12/9/1996<br>terry : 11/18/1996<br>mark : 11/12/1996<br>mark : 11/11/1996<br>mark : 8/29/1996<br>carol : 7/6/1996<br>joanna : 3/22/1996<br>mark : 3/13/1996<br>terry : 3/13/1996<br>mark : 3/13/1996<br>mark : 3/13/1996<br>terry : 3/12/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 10/24/1995<br>terry : 8/10/1995<br>davew : 8/25/1994<br>jason : 7/15/1994<br>mimadm : 5/12/1994<br>warfield : 3/21/1994
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