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Entry
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- *601284 - ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
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- OMIM
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<p>
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<span class="h4">*601284</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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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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<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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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601284">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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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</ul>
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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-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 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="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=ENSG00000139567;t=ENST00000388922" 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=94" 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=601284" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000139567;t=ENST00000388922" 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_000020,NM_001077401,NM_001406487,NM_001406488,NM_001406489,NM_001406490,NM_001406491,NM_001406492,NM_001406493,NM_001406494,NM_001406495,XM_047429901" 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_000020" 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=601284" 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 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=03181&isoform_id=03181_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/ACVRL1" 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/402197,425148,2228562,2295236,3915750,27769258,116734712,116734714,119578615,119578616,119578617,119578618,194373999,194382452,194391166,300216365,300216367,957948851,957948854,2217292100,2239777857,2239784599,2239790138,2239790948,2239796209,2239796225,2239796351,2239796434,2239796759,2419915046" 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/P37023" 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 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=94" 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=ENSG00000139567;t=ENST00000388922" 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=ACVRL1" 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=ACVRL1" 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+94" 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/ACVRL1" 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:94" 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/94" 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=chr12&hgg_gene=ENST00000388922.9&hgg_start=51906944&hgg_end=51923361&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:175" 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:175" 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/acvrl1" 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=601284[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=601284[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/ENSG00000139567" 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=ACVRL1" 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=ACVRL1" 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=ACVRL1" 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="http://www.hhtmutation.org/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ACVRL1&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/PA24496" 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:175" 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/FBgn0003317.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:1338946" 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/ACVRL1#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:1338946" 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/94/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=94" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000897;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000897 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004860;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004860 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-021003-1" 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="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:94" 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=ACVRL1&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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</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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601284
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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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ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
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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">
|
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ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 1; ACVRLK1<br />
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ACTIVIN RECEPTOR-LIKE KINASE 1; ALK1
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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=ACVRL1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ACVRL1</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>
|
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Cytogenetic location: <a href="/geneMap/12/393?start=-3&limit=10&highlight=393">12q13.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:51906944-51923361&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'})">12:51,906,944-51,923,361</a> </span>
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</em>
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</strong>
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<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>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
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</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>
|
|
<th>
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|
Phenotype
|
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
|
|
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<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/393?start=-3&limit=10&highlight=393">
|
|
12q13.13
|
|
</a>
|
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</span>
|
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</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Telangiectasia, hereditary hemorrhagic, type 2
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/600376"> 600376 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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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>
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<div class="btn-group">
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<p>Activin A receptor, type II-like 1 (also called activin receptor-like kinase-1), is a type I cell-surface receptor for the TGF-beta superfamily of ligands (see TGFB1; <a href="/entry/190180">190180</a>). It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail (<a href="#26" class="mim-tip-reference" title="ten Dijke, P., Franzen, P., Yamashita, H., Ichijo, H., Heldin, C. H., Miyazono, K. <strong>Serine/threonine kinase receptors.</strong> Prog. Growth Factor Res. 5: 55-72, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8199354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8199354</a>] [<a href="https://doi.org/10.1016/0955-2235(94)90017-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8199354">ten Dijke et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8199354" 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 PCR-based strategy based on the human activin receptor type II (see <a href="/entry/102581">102581</a>) and C. elegans Daf1 (<a href="/entry/125240">125240</a>) gene products, <a href="#27" class="mim-tip-reference" title="ten Dijke, P., Ichijo, H., Franzen, P., Schulz, P., Saras, J., Toyoshima, H., Heldin, C.-H., Miyazono, K. <strong>Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity.</strong> Oncogene 8: 2879-2887, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8397373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8397373</a>]" pmid="8397373">ten Dijke et al. (1993)</a> identified 4 human cDNA clones encoding putative transmembrane protein serine/threonine kinases, which they denoted activin receptor-like kinases ALK1, ALK2 (<a href="/entry/102576">102576</a>), ALK3 (<a href="/entry/601299">601299</a>), and ALK4 (<a href="/entry/601300">601300</a>). The ALK1 gene encodes a 503-amino acid polypeptide that shares similar domain structures with the other 3 ALK genes they cloned, including hydrophilic cysteine-rich ligand-binding domains, single hydrophobic transmembrane regions, and C-terminal intracellular portions that consist almost entirely of serine/threonine kinase domains. The ALK proteins share approximately 40% sequence identity with activin receptors type II and IIB, TGF-beta receptor (see <a href="/entry/190181">190181</a>), and Daf1 in their kinase domains, but share 60 to 79% sequence identity among themselves, suggesting to <a href="#27" class="mim-tip-reference" title="ten Dijke, P., Ichijo, H., Franzen, P., Schulz, P., Saras, J., Toyoshima, H., Heldin, C.-H., Miyazono, K. <strong>Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity.</strong> Oncogene 8: 2879-2887, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8397373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8397373</a>]" pmid="8397373">ten Dijke et al. (1993)</a> that the ALK gene products form a subfamily of receptor ser/thr kinases. By Northern blot analysis, <a href="#27" class="mim-tip-reference" title="ten Dijke, P., Ichijo, H., Franzen, P., Schulz, P., Saras, J., Toyoshima, H., Heldin, C.-H., Miyazono, K. <strong>Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity.</strong> Oncogene 8: 2879-2887, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8397373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8397373</a>]" pmid="8397373">ten Dijke et al. (1993)</a> showed that ALK1 is most highly expressed in human placenta and lung. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8397373" 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="#4" class="mim-tip-reference" title="Attisano, L., Carcamo, J., Ventura, F., Weis, F. M. B., Massague, J., Wrana, J. L. <strong>Identification of human activin and TGF-beta type I receptors that form heteromeric kinase complexes with type II receptors.</strong> Cell 75: 671-680, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8242742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8242742</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90488-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8242742">Attisano et al. (1993)</a> likewise cloned a human cDNA encoding ACVRL1 (termed TSR1 by them) and presented similar tissue localization data. They further characterized the gene product and concluded that the ACVRL1 type I cell surface receptor is a transmembrane protein kinase that associates with type II receptors to generate diverse heteromeric ser/thr kinase complexes of different signaling capacities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8242742" 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="#6" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. <strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong> Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>] [<a href="https://doi.org/10.1086/513903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245985">Berg et al. (1997)</a> demonstrated that the coding region of the ALK1 gene is contained within 9 exons, spanning more than 15 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245985" 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 somatic cell hybrid mapping, <a href="#22" class="mim-tip-reference" title="Roijer, E., Miyazono, K., Astrom, A.-K., Geurts van Kessel, A., ten Dijke, P., Stenman, G. <strong>Chromosomal localization of three human genes encoding members of the TGF-beta superfamily of type I serine/threonine kinase receptors.</strong> Mammalian Genome 9: 266-268, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501322</a>] [<a href="https://doi.org/10.1007/s003359900745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501322">Roijer et al. (1998)</a> mapped the ACVRL1 gene to chromosome 12. By fluorescence in situ hybridization, they localized the gene to 12q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501322" 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="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> noted that the high expression of ALK1 in endothelial cells and other highly vascularized tissues such as lung and placenta and its low expression in other cells and tissues parallels that of endoglin (<a href="/entry/131195">131195</a>), which is defective in hereditary hemorrhagic telangiectasia type 1 (HHT1; <a href="/entry/187300">187300</a>), also called Osler-Rendu-Weber disease (ORW1). Endoglin is a homodimeric endothelial cell membrane protein that binds TGF-beta. ALK1 is a type I receptor which can bind TGF-beta or activin (<a href="/entry/147290">147290</a>) when coexpressed with the corresponding activin type II receptor (<a href="/entry/102581">102581</a>). They also presented a model for TGF-beta receptor functions involved in Osler-Rendu-Weber disease. They suggested that endoglin sequesters TGF-beta and presents the ligand to the signaling complex of ALK1 and a type II receptor. Presumably endoglin and ALK1 cause ORW1 by disruption of this receptor complex involved in TGF-beta signal transduction. They stated that defects in a type II receptor within this complex might also be expected to cause the phenotype of ORW1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 COS-1 transfected cells, <a href="#3" class="mim-tip-reference" title="Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. <strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong> Hum. Molec. Genet. 9: 1227-1237, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767348</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767348">Abdalla et al. (2000)</a> determined that ALK1 was found in TGFB1 and -B3 (<a href="/entry/190230">190230</a>) receptor complexes in association with endoglin and TGFBR2 (<a href="/entry/190182">190182</a>), but not in activin receptor complexes containing endoglin. In human umbilical vein endothelial cells (HUVEC), ALK1 was not detectable in TGFB1 or -B3 receptor complexes. However, in the absence of ligand, ALK1 and endoglin interactions were observed by immunoprecipitation/Western blot in HUVEC from normal as well as HHT1 and HHT2 patients. The authors hypothesized that a transient association between ALK1 and endoglin is required at a critical level to ensure vessel wall integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767348" 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>Hereditary hemorrhagic telangiectasia and cerebral cavernous malformations (see <a href="/entry/116860">116860</a>) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to <a href="#17" class="mim-tip-reference" title="Marchuk, D. A., Srinivasan, S., Squire, T. L., Zawistowski, J. S. <strong>Vascular morphogenesis: tales of two syndromes.</strong> Hum. Molec. Genet. 12(R1): R97-R112, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668602</a>] [<a href="https://doi.org/10.1093/hmg/ddg103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668602">Marchuk et al. (2003)</a> that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, ALK1, KRIT1 (<a href="/entry/604214">604214</a>), and endoglin, in the genetic control of angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668602" 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>By yeast 2-hybrid analysis and coimmunoprecipitation experiments, <a href="#16" class="mim-tip-reference" title="Lux, A., Beil, C., Majety, M., Barron, S., Gallione, C. J., Kuhn, H.-M., Berg, J. N., Kioschis, P., Marchuk, D. A., Hafner, M. <strong>Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1.</strong> J. Biol. Chem. 280: 8482-8493, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15611116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15611116</a>] [<a href="https://doi.org/10.1074/jbc.M409197200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15611116">Lux et al. (2005)</a> determined that 2 proteins encoded by the PEG10 gene (<a href="/entry/609810">609810</a>), PEG10-RF1 and PEG10-RF1/RF2, interacted with the cytoplasmic domain of ALK1. Immunoprecipitation analysis detected interaction between PEG10-RF1 and several other members of the TGF-beta receptor family following cotransfection in COS-1 cells, but only ALK1 showed high specific interaction with PEG10-RF1. Following expression in a mink lung cell line, PEG10-RF1 inhibited signaling through ALK1. Overexpression of either ALK1 or PEG10-RF1 alone in several mammalian cell lines did not alter cell morphology, but cotransfection led to colocalization of ALK1 and PEG10-RF1 along several intracellular structures and cellular changes leading to neuron-like morphology, including dendrite-like contacts between cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15611116" 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="#8" class="mim-tip-reference" title="David, L., Mallet, C., Mazerbourg, S., Feige, J.-J., Bailly, S. <strong>Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.</strong> Blood 109: 1953-1961, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17068149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17068149</a>] [<a href="https://doi.org/10.1182/blood-2006-07-034124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17068149">David et al. (2007)</a> identified BMP9 (GDF2; <a href="/entry/605120">605120</a>) as a ligand for ALK1. BMP9 induced phosphorylation of SMAD1 (<a href="/entry/601595">601595</a>)/SMAD5 (<a href="/entry/603110">603110</a>)/SMAD8 (<a href="/entry/603295">603295</a>) in human microvascular endothelial cells via ALK1. Overexpression of the coreceptor endoglin potentiated the BMP9 response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17068149" 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><strong><em>Hereditary Hemorrhagic Telangiectasia Type 2</em></strong></p><p>
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In affected patients from 3 families with hereditary hemorrhagic telangiectasia-2 (HHT2; <a href="/entry/600376">600376</a>), <a href="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> identified mutations in the ALK1 gene (<a href="#0001">601284.0001</a>-<a href="#0003">601284.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 6 of 6 families with HHT in which either linkage to 12q13 was demonstrated or linkage to 9q33 had been excluded <a href="#6" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. <strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong> Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>] [<a href="https://doi.org/10.1086/513903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245985">Berg et al. (1997)</a> identified mutations in the ALK1 gene (see, e.g., <a href="#0004">601284.0004</a>). Mutations were also found in 3 of 6 patients from families in which available linkage data were insufficient to allow certainty with regard to the locus involved. In 2 cases in which premature termination codons were found in genomic DNA, the mutant mRNA was either not present or present at barely detectable levels, suggesting that mutations in ALK1 are functionally null alleles and probably rule out a dominant-negative effect as the pathogenetic mechanism of HHT2. <a href="#6" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. <strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong> Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>] [<a href="https://doi.org/10.1086/513903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245985">Berg et al. (1997)</a> discussed the possibility of a second hit, according to the Knudson model for tumor suppressor genes, in the pathogenesis of the local lesions. The slow enlargement of lesions suggested that if ALK1 requires a somatic second mutation for vascular lesion formation, then it is not acting as a tumor suppressor gene. Since TGF-beta signaling in endothelial cells modulates vascular remodeling by inducing changes in the extracellular matrix, complete loss of ALK1 signaling may induce remodeling of the vascular bed, rather than directly affecting the rate of endothelial cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245985" 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 families with HHT2, <a href="#3" class="mim-tip-reference" title="Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. <strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong> Hum. Molec. Genet. 9: 1227-1237, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767348</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767348">Abdalla et al. (2000)</a> reported 3 additional ALK1 missense mutations, one of which led to a G48E/A49P (<a href="#0005">601284.0005</a>) substitution. Using a polyclonal antibody to ALK1, <a href="#3" class="mim-tip-reference" title="Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. <strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong> Hum. Molec. Genet. 9: 1227-1237, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767348</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767348">Abdalla et al. (2000)</a> measured ALK1 expression on HUVEC of newborns from HHT2 families. ALK1 levels were specifically reduced in 3 HUVEC samples with ALK1 missense mutant codons, and normal in 2 newborns not carrying the mutations. Levels were normal in a HUVEC sample with deletion of S232 in the ATP binding site of ALK1. The authors concluded that HHT2 can be associated either with reduction in protein level or protein activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767348" 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="#12" class="mim-tip-reference" title="Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A. <strong>Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.</strong> Am. J. Med. Genet. 98: 298-302, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170071</a>] [<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<298::aid-ajmg1093>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170071">Kjeldsen et al. (2001)</a> used denaturing gradient gel electrophoresis (DGGE) to identify mutations in the ALK1 gene in 2 families with hereditary hemorrhagic telangiectasia. In a family with an ile398-to-asn mutation (I398N; <a href="#0006">601284.0006</a>) there was a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding, whereas in a family with an arg374-to-thr mutation (R374T; <a href="#0007">601284.0007</a>), no individuals had pulmonary arteriovenous malformations and only 1 patient had a history of severe gastrointestinal bleeding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" 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="Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. <strong>Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114496</a>] [<a href="https://doi.org/10.1136/jmg.39.7.e39" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114496">Olivieri et al. (2002)</a> analyzed exons 3, 7, and 8 of the ACVRL1 gene in 52 Italian probands with HHT and identified heterozygosity for 13 different mutations in 16 of the probands, including an R67W substitution (<a href="#0017">601284.0017</a>) in 2 probands. The authors noted that a different mutation involving the same residue, an R67Q substitution, previously had been reported in an HHT patient by <a href="#6" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. <strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong> Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>] [<a href="https://doi.org/10.1086/513903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245985">Berg et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9245985+12114496" 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 affected members of 16 families with HHT2, <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a> identified 14 ALK1 mutations, including 9 that were novel. This brought to 36 the number of ALK1 mutations associated with HHT2. The mutations showed clustering in exons 8 and 3, followed in frequency in exons 4 and 7. After generating a model based on the homologous ALK5 kinase domain, <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a> concluded that the 11 missense mutations modify conserved residues by altering polarity, charge, hydrophobicity, and/or size, thereby leading to misfolded and nonfunctional proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700602" 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 8 unrelated probands with HHT and HHT-related pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified 7 ALK1 mutations (see, e.g., <a href="#0001">601284.0001</a>; <a href="#0007">601284.0007</a>; <a href="#0011">601284.0011</a>-<a href="#0013">601284.0013</a>), 3 of which were novel, clustered in exons 5 to 10. Normally membrane bound, most of the ALK1 mutant proteins remained in the endoplasmic reticulum. The authors concluded that pulmonary arterial hypertension is an important disease complication of HHT, most commonly associated with ALK1 receptor signaling defects with frequent mutations in exon 8. One patient reported by <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> who had primary pulmonary hypertension without known features of HHT2 had a mutation in the GS region of the ACVRL1 protein. The patient had died, and retrospective analysis confirmed the diagnosis of primary pulmonary hypertension. Parents or surviving relatives were not available for study. <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> noted that no disease-related mutations of the GS region had previously been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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="Loscalzo, J. <strong>Genetic clues to the cause of primary pulmonary hypertension. (Editorial)</strong> New Eng. J. Med. 345: 367-371, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484696</a>] [<a href="https://doi.org/10.1056/NEJM200108023450511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484696">Loscalzo (2001)</a> reviewed, with a hypothetical model, the role of mutations in the BMPR2 (<a href="/entry/600799">600799</a>) and ALK1 genes in the development of primary pulmonary hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484696" 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 160 unrelated cases of HHT, <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> screened the coding sequences of the ENG (<a href="/entry/131195">131195</a>) and ALK1 genes. Germline mutations were identified in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in ALK1. <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> noted that a 1-bp insertion (<a href="#0014">601284.0014</a>) previously identified by <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a>, was found in 17 unrelated patients who shared a common haplotype and were from the same region of France as the patients reported by <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a>, strongly suggesting a founder effect. In 1, 2, and 7 patients, <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> identified 3 missense mutations involving codon arg411: R411Q (<a href="#0001">601284.0001</a>), R411P (<a href="#0015">601284.0015</a>), and R411W (<a href="#0009">601284.0009</a>), respectively. Haplotype analysis favored both a founder effect and a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12700602+15024723" 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="#2" class="mim-tip-reference" title="Abdalla, S. A., Letarte, M. <strong>Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.</strong> J. Med. Genet. 43: 97-110, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15879500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15879500</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15879500[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/10.1136/jmg.2005.030833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15879500">Abdalla and Letarte (2006)</a> tabulated the known ALK1 mutations causing HHT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15879500" 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="#5" class="mim-tip-reference" title="Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.-S., Gedge, F., Tang, W., Coon, H., Mao, R. <strong>Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.</strong> Am. J. Med. Genet. 140A: 463-470, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470787</a>] [<a href="https://doi.org/10.1002/ajmg.a.31101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470787">Bayrak-Toydemir et al. (2006)</a> identified mutations in 26 (76%) of 34 kindreds with HHT. Fourteen (54%) mutations were in the ENG gene, consistent with HHT1, and 12 (46%) were in the ACVRL1 gene, consistent with HHT2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470787" 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="Wehner, L.-E., Folz, B. J., Argyriou, L., Twelkemeyer, S., Teske, U., Geisthoff, U. W., Werner, J. A., Engel, W., Nayernia, K. <strong>Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations.</strong> Clin. Genet. 69: 239-245, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542389</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00574.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542389">Wehner et al. (2006)</a> identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. A review of all mutations reported to date in the ACVRL1 gene showed that approximately 64% were in exons 3, 7, and 8. Analysis of genotype/phenotype correlations was consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16542389" 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>To explore the mechanism underlying the effect of HHT-related ALK1 mutations on receptor activity, <a href="#9" class="mim-tip-reference" title="Gu, Y., Jin, P., Zhang, L., Zhao, X., Gao, X., Ning, Y., Meng, A., Chen, Y.-G. <strong>Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia.</strong> Blood 107: 1951-1954, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16282348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16282348</a>] [<a href="https://doi.org/10.1182/blood-2005-05-1834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16282348">Gu et al. (2006)</a> generated 11 such mutants and investigated their signaling activities using reporter assay in mammalian cells and examined their effect on zebrafish embryogenesis. They showed that some of HHT2-related mutations generated a dominant-negative effect where the others gave rise to a null phenotype via loss of protein expression or receptor activity. These data indicated that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16282348" 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="Olivieri, C., Pagella, F., Semino, L., Lanzarini, L., Valacca, C., Pilotto, A., Corno, S., Scappaticci, S., Manfredi, G., Buscarini, E., Danesino, C. <strong>Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies.</strong> J. Hum. Genet. 52: 820-829, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17786384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17786384</a>] [<a href="https://doi.org/10.1007/s10038-007-0187-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17786384">Olivieri et al. (2007)</a> identified 50 different mutations in the ACVRL1 gene in 72 of 101 Italian patients with HHT. Twenty-six different ENG mutations were identified in 29 of the 101 patients. The findings were consistent with a higher frequency of ACVRL1 mutations compared to ENG mutations in HHT patients of Mediterranean ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17786384" 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 4 of 45 probands with clinical HHT and negative results on direct sequencing, <a href="#24" class="mim-tip-reference" title="Shoukier, M., Teske, U., Weise, A., Engel, W., Argyriou, L. <strong>Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia.</strong> Clin. Genet. 73: 320-330, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18312453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18312453</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00968.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18312453">Shoukier et al. (2008)</a> identified 4 different large heterozygous deletions involving the ACVRL1 gene using quantitative real-time polymerase chain reaction (qRT-PCR). The results were confirmed by multiplex ligation-dependent probe amplification (MLPA). Affected members of 2 families had deletion of the entire ACVRL1 gene. One of these deletions spanned at least 216 kb and included 5 neighboring genes, including ACVR1B, GRASP (<a href="/entry/612027">612027</a>), and NR4A1 (<a href="/entry/139139">139139</a>). The proband who carried this large deletion had no additional symptoms besides HHT, indicating that heterozygous loss of these genes has no obvious phenotypic effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18312453" 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 cellular expression studies, <a href="#21" class="mim-tip-reference" title="Ricard, N., Bidart, M., Mallet, C., Lesca, G., Giraud, S., Prudent, R., Feige, J.-J., Bailly, S. <strong>Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations.</strong> Blood 116: 1604-1612, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20501893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20501893</a>] [<a href="https://doi.org/10.1182/blood-2010-03-276881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20501893">Ricard et al. (2010)</a> found that none of 15 different pathogenic ALK1 mutants responded to stimulation with BMP9, as measure by phosphorylation of SMAD1 and SMAD5. Eleven mutations affecting the intracellular kinase domain of ALK1 were properly expressed at the cell surface and were able to bind BMP9. Three mutations located in the extracellular domain of ALK1 did not bind BMP9. None of the ALK1 mutants showed a dominant-negative effect on wildtype ALK1, indicating that they result in functional haploinsufficiency. <a href="#21" class="mim-tip-reference" title="Ricard, N., Bidart, M., Mallet, C., Lesca, G., Giraud, S., Prudent, R., Feige, J.-J., Bailly, S. <strong>Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations.</strong> Blood 116: 1604-1612, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20501893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20501893</a>] [<a href="https://doi.org/10.1182/blood-2010-03-276881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20501893">Ricard et al. (2010)</a> suggested that functional analysis of BMP9 responses can be used as a diagnostic tool to evaluate ALK1 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20501893" 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 whole-genome sequencing of 35 patients with HHT among 13 families and next-generation sequencing of a custom panel of genes that had been associated with HHT among 87 unrelated patients with suspected HHT, <a href="#31" class="mim-tip-reference" title="Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P. <strong>Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 55: 824-830, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244195</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30244195">Wooderchak-Donahue et al. (2018)</a> identified 8 patients with novel noncoding heterozygous ACVRL1 gene variants that disrupt splicing. In 1 family, an affected mother and son had an ACVRL1 intron 9:chromosome 3 translocation, t(12,3)(q13,p21), the first reported translocation to cause HHT. In the other 7 families, the variants were located within an approximately 300-bp CT-rich hotspot region of intron 9 (see, e.g., <a href="#0016">601284.0016</a>) that disrupted splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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>Somatic Mutation</em></strong></p><p>
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By SSCP analysis, <a href="#7" class="mim-tip-reference" title="D'Abronzo, F. H., Swearingen, B., Klibanski, A., Alexander, J. M. <strong>Mutational analysis of activin/transforming growth factor-beta type I and type II receptor kinases in human pituitary tumors.</strong> J. Clin. Endocr. Metab. 84: 1716-1721, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323406</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323406">D'Abronzo et al. (1999)</a> examined 2 intracellular regions required for type I receptor signaling by human ALK1-5 type I receptors as well as the entire coding region of 2 activin type II receptors and the TGF-beta type II receptor (<a href="/entry/190182">190182</a>) in 64 human pituitary tumors. One patient with a gonadotroph tumor had a confirmed germline mutation in the ALK1 gene within kinase subdomains X-XI. The authors concluded that somatic mutations within these intracellular kinase regions of type I/type II receptors are rare in human pituitary tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323406" 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>The mature circulatory system is composed of 2 parallel, yet distinct, vascular networks that carry blood to and from the heart. Studies had suggested that endothelial tubes are specified as arteries or veins at the earliest stages of angiogenesis, before the onset of circulation. To understand the molecular basis for arterial-venous identity, <a href="#29" class="mim-tip-reference" title="Urness, L. D., Sorensen, L. K., Li, D. Y. <strong>Arteriovenous malformations in mice lacking activin receptor-like kinase-1.</strong> Nature Genet. 26: 328-331, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062473</a>] [<a href="https://doi.org/10.1038/81634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062473">Urness et al. (2000)</a> focused on HHT, wherein arterial and venous beds fail to remain distinct. At the earliest stage of vascular development, mice lacking Acvrl1 developed large shunts between arteries and veins, downregulated arterial Efnb2 (<a href="/entry/600527">600527</a>), and failed to confine intravascular hematopoiesis to arteries. These mice died by midgestation with severe arteriovenous malformations resulting from fusion of major arteries and veins. The observations indicated that Acvrl1 is required for developing distinct arterial and venous vascular beds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062473" 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="Srinivasan, S., Hanes, M. A., Dickens, T., Porteous, M. E. M., Oh, S. P., Hale, L. P., Marchuk, D. A. <strong>A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.</strong> Hum. Molec. Genet. 12: 473-482, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588795</a>] [<a href="https://doi.org/10.1093/hmg/ddg050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588795">Srinivasan et al. (2003)</a> created mice heterozygous for a loss-of-function mutation in Acvrl1. The mice developed age-dependent vascular lesions in the skin, extremities, oral cavity, and internal organs (lung, liver, intestine, spleen, and brain), as well as occult gastrointestinal bleeding. Major histopathologic features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage, and fibrosis. An Acvrl1 +/- mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588795" 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 a novel Alk1 null mutant mouse line in which a beta-galactosidase (see <a href="/entry/230500">230500</a>) reporter gene (lacZ) was inserted into the Alk1 locus, <a href="#23" class="mim-tip-reference" title="Seki, T., Yun, J., Oh, S. P. <strong>Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.</strong> Circ. Res. 93: 682-689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970115</a>] [<a href="https://doi.org/10.1161/01.RES.0000095246.40391.3B" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970115">Seki et al. (2003)</a> showed that Alk1 was predominantly expressed in developing arterial, but not venous, endothelium. Alk1 expression was greatly diminished in adult arteries, but was induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis, and in existing arteries in areas of increased blood flow. This suggested a role of Alk1 signaling in arterialization and remodeling of arteries. <a href="#23" class="mim-tip-reference" title="Seki, T., Yun, J., Oh, S. P. <strong>Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.</strong> Circ. Res. 93: 682-689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970115</a>] [<a href="https://doi.org/10.1161/01.RES.0000095246.40391.3B" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970115">Seki et al. (2003)</a> concluded that, contrary to the view of HHT as a venous disease, their findings suggested that arterioles rather than venules are the primary vessels affected by the loss of an ALK1 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970115" 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>.0001 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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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> rs121909284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909284;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/rs121909284?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=rs121909284" 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=rs121909284" 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=RCV000008726 OR RCV000008727 OR RCV000522363 OR RCV002371767" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008726, RCV000008727, RCV000522363, RCV002371767" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008726...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> identified a 1232G-A transition in the ACVRL1 gene that was predicted to result in an arg411-to-gln (R411Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 French patient with HHT2, <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> identified the R411Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024723" 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 26-year-old woman with familial hereditary hemorrhagic telangiectasia-related primary pulmonary hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified the R411Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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">rs28936399 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936399;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=rs28936399" 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=rs28936399" 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=RCV000008728 OR RCV002444423" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008728, RCV002444423" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008728...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> identified a 1127T-G transversion in the ALK1 gene that was predicted to cause a met376-to-arg (M376R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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">rs387906391 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906391;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=rs387906391" 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=rs387906391" 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=RCV000230219 OR RCV000506933 OR RCV001507805 OR RCV002372240" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000230219, RCV000506933, RCV001507805, RCV002372240" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000230219...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> identified a 3-bp deletion (their cDNA nucleotides 696-698) in the ALK1 gene, resulting in deletion of 1 of 2 adjacent serine residues that are conserved in most of the type I TGF-beta receptor family members from mammals to Drosophila. The deletion occurred in the kinase subdomain II. <a href="#11" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. <strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong> Nature Genet. 13: 189-195, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>] [<a href="https://doi.org/10.1038/ng0696-189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640225">Johnson et al. (1996)</a> also identified this deletion in a few unaffected individuals, all of whom showed the disease haplotype throughout the entire candidate interval; they were presumed to be nonpenetrant for HHT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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">rs121909285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909285;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=rs121909285" 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=rs121909285" 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=RCV000008730 OR RCV001557555 OR RCV002390097" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008730, RCV001557555, RCV002390097" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008730...</a>
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<p>In a patient with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#6" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. <strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong> Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>] [<a href="https://doi.org/10.1086/513903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245985">Berg et al. (1997)</a> identified a G-to-T transversion in the ALK1 gene, resulting in a trp150-to-cys (W150C) substitution in the extracellular domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245985" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
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ACVRL1, GLY48GLU AND ALA49PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606632;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=rs267606632" 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=rs267606632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs267606633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606633;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/rs267606633?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=rs267606633" 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=rs267606633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906392 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906392;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=rs387906392" 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=rs387906392" 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=RCV000008731 OR RCV000144433 OR RCV000144434 OR RCV002390302" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008731, RCV000144433, RCV000144434, RCV002390302" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008731...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#3" class="mim-tip-reference" title="Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. <strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong> Hum. Molec. Genet. 9: 1227-1237, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767348</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767348">Abdalla et al. (2000)</a> identified a complex mutation in exon 3 of the ALK1 gene, consisting of a G143A transition, deletion of G145, and insertion of T147. The mutation converts adjacent amino acids glycine48 to glutamic acid (G48E) and alanine49 to proline (A49P) in the extracellular domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767348" 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">rs121909286 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909286;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=rs121909286" 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=rs121909286" 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=RCV000008732" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008732" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008732</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#12" class="mim-tip-reference" title="Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A. <strong>Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.</strong> Am. J. Med. Genet. 98: 298-302, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170071</a>] [<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<298::aid-ajmg1093>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170071">Kjeldsen et al. (2001)</a> identified an 1193T-A transversion in exon 8 of the ALK1 gene, resulting in an ile398-to-asn (I398N) substitution. Affected members had a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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"><span class="text-primary">●</span> rs28936401 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936401;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/rs28936401?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=rs28936401" 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=rs28936401" 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=RCV000008733 OR RCV000008734 OR RCV000330901 OR RCV002433448 OR RCV004547469" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008733, RCV000008734, RCV000330901, RCV002433448, RCV004547469" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008733...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#12" class="mim-tip-reference" title="Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A. <strong>Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.</strong> Am. J. Med. Genet. 98: 298-302, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170071</a>] [<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<298::aid-ajmg1093>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170071">Kjeldsen et al. (2001)</a> identified an 1120C-T transition in exon 8 of the ALK1 gene, resulting in an arg374-to-trp (R374W) substitution. No affected patients had pulmonary arteriovenous malformations, and only 1 patient had a history of severe gastrointestinal bleeding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" 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 population-based study of primarily French HHT2 patients, <a href="#13" class="mim-tip-reference" title="Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H. <strong>Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.</strong> Europ. J. Hum. Genet. 16: 742-749, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285823</a>] [<a href="https://doi.org/10.1038/ejhg.2008.3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285823">Lesca et al. (2008)</a> showed that the R374W mutation associated with a shared ancestral haplotype in a subset of patients, suggesting a founder effect with the mutation arising approximately 300 years ago. In other patients, the mutation was related to different independent mutation events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285823" 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 41-year-old woman with hereditary hemorrhagic telangiectasis-related pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified the R374W mutation. The patient had an atrial septal defect repaired before the onset of significantly raised pulmonary artery pressure, and also had a sib with primary pulmonary hypertension (see <a href="/entry/178600">178600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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">rs387906393 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906393;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=rs387906393" 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=rs387906393" 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=RCV000008735 OR RCV000008736 OR RCV000755791 OR RCV002390098" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008735, RCV000008736, RCV000755791, RCV002390098" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008735...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia-2 (HHT2; <a href="/entry/600376">600376</a>), <a href="#28" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. <strong>Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.</strong> New Eng. J. Med. 345: 325-334, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484689</a>] [<a href="https://doi.org/10.1056/NEJM200108023450503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484689">Trembath et al. (2001)</a> identified a 3-bp deletion (del759-761) in exon 6 of the ACVRL1 gene, resulting in deletion of asp254. Three members had isolated HHT and 2 members had both HHT and pulmonary arterial hypertension, 1 of whom had pulmonary arteriovenous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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">rs121909287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909287;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=rs121909287" 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=rs121909287" 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=RCV000008737 OR RCV000008738 OR RCV000199381 OR RCV002362571" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008737, RCV000008738, RCV000199381, RCV002362571" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008737...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#28" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. <strong>Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.</strong> New Eng. J. Med. 345: 325-334, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484689</a>] [<a href="https://doi.org/10.1056/NEJM200108023450503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484689">Trembath et al. (2001)</a> identified an arg411-to-trp (R411W) mutation in exon 8 of the ACVRL1 gene. One patient had HHT and pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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 7 unrelated French patients with HHT2, <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> identified the R411W mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024723" 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 population-based study of primarily French HHT2 patients, <a href="#13" class="mim-tip-reference" title="Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H. <strong>Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.</strong> Europ. J. Hum. Genet. 16: 742-749, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285823</a>] [<a href="https://doi.org/10.1038/ejhg.2008.3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285823">Lesca et al. (2008)</a> showed that the R411W mutation associated with a shared ancestral haplotype in a subset of patients, suggesting a founder effect with the mutation arising approximately 300 years ago. In other patients, the mutation was related to different independent mutation events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285823" 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>.0010 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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"><span class="text-primary">●</span> rs121909288 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909288;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/rs121909288?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=rs121909288" 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=rs121909288" 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=RCV000008739 OR RCV000008740 OR RCV000507762 OR RCV001003756 OR RCV001564363 OR RCV002390099" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008739, RCV000008740, RCV000507762, RCV001003756, RCV001564363, RCV002390099" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008739...</a>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#28" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. <strong>Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.</strong> New Eng. J. Med. 345: 325-334, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484689</a>] [<a href="https://doi.org/10.1056/NEJM200108023450503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484689">Trembath et al. (2001)</a> identified an arg484-to-trp (R484W) mutation in exon 10 of the ACVRL1 gene. Two patients had isolated HHT, 2 had isolated pulmonary arterial hypertension, and 1 had both HHT and pulmonary hypertension (see <a href="/entry/600376">600376</a>). <a href="#28" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. <strong>Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.</strong> New Eng. J. Med. 345: 325-334, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484689</a>] [<a href="https://doi.org/10.1056/NEJM200108023450503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484689">Trembath et al. (2001)</a> noted that the arginine residue at this position is conserved in mouse and human ACVRL1 and in several human paralogs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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>.0011 PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED</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">rs28936687 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936687;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=rs28936687" 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=rs28936687" 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=RCV000008741 OR RCV001001392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008741, RCV001001392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008741...</a>
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<p>In a 56-year-old woman with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified a 632G-A transition in exon 6 of the ACVRL1 gene, resulting in a gly211-to-asp (G211D) substitution. The patient had a 6-month exposure to an appetite suppressant, at least 8 years before the onset of symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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>.0012 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28936688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936688;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=rs28936688" 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=rs28936688" 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=RCV000008742 OR RCV000008743 OR RCV001507809 OR RCV001844010 OR RCV002381244" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008742, RCV000008743, RCV001507809, RCV001844010, RCV002381244" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008742...</a>
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<p>In 2 unrelated patients with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified a 1031G-A transition in exon 7 of the ACVRL1 gene, resulting in a cys344-to-tyr (C344Y) substitution. This mutation had been reported previously by <a href="#3" class="mim-tip-reference" title="Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. <strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong> Hum. Molec. Genet. 9: 1227-1237, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767348</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767348">Abdalla et al. (2000)</a> in patients with isolated hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10767348+14684682" 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>.0013 PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008744 OR RCV002345234 OR RCV005089210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008744, RCV002345234, RCV005089210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008744...</a>
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<p>In a 29-year-old woman with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see <a href="/entry/600376">600376</a>), <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. <strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>] [<a href="https://doi.org/10.1136/jmg.40.12.865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684682">Harrison et al. (2003)</a> identified a 1196G-C transversion in exon 8 of the ACVRL1 gene, resulting in a trp399-to-ser (W399S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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>.0014 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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">rs387906394 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906394;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=rs387906394" 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=rs387906394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia-2 (HHT2; <a href="/entry/600376">600376</a>), <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a> identified a 1-bp insertion in exon 8 of the ACVRL1 gene, 1113insG, resulting in a frameshift at codon 371 and the addition of 51 novel amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700602" 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 17 of 160 unrelated patients with HHT2, <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> identified the 1113insG mutation, which they referred to as a 1-bp duplication (1112dupG). The 17 patients shared a common haplotype and all originated from the Rhone-Alpes region of France, strongly suggesting a founder effect. <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> stated that the family reported by <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. <strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong> Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700602</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700602">Abdalla et al. (2003)</a> originated from the same region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12700602+15024723" 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="#13" class="mim-tip-reference" title="Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H. <strong>Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.</strong> Europ. J. Hum. Genet. 16: 742-749, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285823</a>] [<a href="https://doi.org/10.1038/ejhg.2008.3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285823">Lesca et al. (2008)</a> identified the 1-bp insertion (1113insG), which they called 1112dupG, in the ACVRL1 gene as the most common mutation responsible for HHT2 (<a href="/entry/600376">600376</a>) in 35 of 96 French and Italian probands with the disorder. Haplotype analysis indicated a founder effect, estimated to have occurred about 325 years ago in an inhabitant of the Haut-Jura mountains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285823" 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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ACVRL1, ARG411PRO
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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> rs121909284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909284;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/rs121909284?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=rs121909284" 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=rs121909284" 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=RCV000008746" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008746" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008746</a>
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<p>In 2 unrelated French patients with hereditary hemorrhagic telangiectasia-2 (HHT2; <a href="/entry/600376">600376</a>), <a href="#14" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. <strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong> Hum. Mutat. 23: 289-299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>] [<a href="https://doi.org/10.1002/humu.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024723">Lesca et al. (2004)</a> identified a 1232G-C transversion in exon 8 of the ACVRL1 gene, resulting in an arg411-to-pro (R411P) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024723" 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"><span class="text-primary">●</span> rs111710113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111710113;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/rs111710113?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=rs111710113" 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=rs111710113" 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 4-generation family (family 1) with hereditary hemorrhagic telangiectasia-2 (HHT2; <a href="/entry/600376">600376</a>), <a href="#31" class="mim-tip-reference" title="Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P. <strong>Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 55: 824-830, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244195</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30244195">Wooderchak-Donahue et al. (2018)</a> identified a novel heterozygous deep intronic variant (c.1378-216C-G) in the ACVRL1 gene. The mutation, which was identified by whole-genome sequencing and confirmed by Sanger sequencing, was predicted by splice site prediction programs to create a new splice acceptor site and alter splicing. RNA studies confirmed partial retention of intron 9 in the aberrantly spliced product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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 2 apparently unrelated Italian probands (MC and P301) with hereditary hemorrhagic telangiectasia (HHT2; <a href="/entry/600376">600376</a>), <a href="#18" class="mim-tip-reference" title="Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. <strong>Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.</strong> J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114496</a>] [<a href="https://doi.org/10.1136/jmg.39.7.e39" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114496">Olivieri et al. (2002)</a> identified heterozygosity for a c.199C-T transversion in exon 3 of the ACVRL1 gene, resulting in an arg67-to-trp (R67W) substitution at a conserved residue. The proband P301 was a member of the large Italian family originally studied by <a href="#20" class="mim-tip-reference" title="Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C. <strong>Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.</strong> J. Med. Genet. 33: 441-443, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782041</a>] [<a href="https://doi.org/10.1136/jmg.33.6.441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782041">Piantanida et al. (1996)</a>; no relationship could be found between the 2 families up to the great-grandparents, but the authors noted that both family names originated from closely related geographical areas in northern Italy. Because the probands also shared alleles at the ACVRL1 intronic D12S167 polymorphism and at the common exon 3 polymorphism (cp3), the authors concluded that a common ancestor was very likely. Extensive liver involvement in the large family was confirmed, and intrahepatic arteriovenous shunts were also present in the other family sharing the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8782041+12114496" 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="https://doi.org/10.1016/0092-8674(93)90488-c" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470787</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470787" 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/10.1182/blood-2006-07-034124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2005-05-1834" target="_blank">Full Text</a>]
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Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F. Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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/10.1136/jmg.40.12.865" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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/10.1038/ng0696-189" target="_blank">Full Text</a>]
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Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A.
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<strong>Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" 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/10.1002/1096-8628(20010201)98:4<298::aid-ajmg1093>3.0.co;2-k" target="_blank">Full Text</a>]
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Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H.
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<strong>Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285823</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285823" 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/10.1038/ejhg.2008.3" target="_blank">Full Text</a>]
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Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S.
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<strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong>
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<strong>Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.</strong>
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J. Med. Genet. 55: 824-830, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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/10.1136/jmedgenet-2018-105561" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 11/22/2024
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Sonja A. Rasmussen - updated : 02/05/2019<br>Cassandra L. Kniffin - updated : 6/13/2011<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Cassandra L. Kniffin - updated : 9/5/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Victor A. McKusick - updated : 6/8/2006<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Victor A. McKusick - updated : 3/9/2006<br>Patricia A. Hartz - updated : 1/25/2006<br>George E. Tiller - updated : 3/3/2005<br>George E. Tiller - updated : 1/5/2005<br>Victor A. McKusick - updated : 5/5/2004<br>Cassandra L. Kniffin - reorganized : 4/29/2004<br>Cassandra L. Kniffin - updated : 4/12/2004<br>Natalie E. Krasikov - updated : 3/30/2004<br>Marla J. F. O'Neill - updated : 3/15/2004<br>Victor A. McKusick - updated : 9/20/2001<br>Sonja A. Rasmussen - updated : 3/12/2001<br>Victor A. McKusick - updated : 10/27/2000<br>George E. Tiller - updated : 7/10/2000<br>John A. Phillips, III - updated : 6/5/2000<br>Alan F. Scott - updated : 6/5/1998<br>Victor A. McKusick - updated : 8/20/1997<br>Mark H. Paalman - updated : 6/13/1996
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Victor A. McKusick : 5/29/1996
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alopez : 11/22/2024
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carol : 02/24/2020<br>carol : 08/22/2019<br>carol : 02/06/2019<br>carol : 02/05/2019<br>carol : 12/07/2017<br>carol : 12/06/2017<br>carol : 09/16/2016<br>terry : 08/17/2012<br>wwang : 6/24/2011<br>ckniffin : 6/13/2011<br>wwang : 9/24/2008<br>ckniffin : 9/16/2008<br>wwang : 9/9/2008<br>ckniffin : 9/5/2008<br>wwang : 3/19/2008<br>ckniffin : 2/29/2008<br>wwang : 4/4/2007<br>alopez : 6/9/2006<br>terry : 6/8/2006<br>wwang : 5/3/2006<br>ckniffin : 4/27/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>alopez : 3/14/2006<br>terry : 3/9/2006<br>mgross : 1/25/2006<br>alopez : 3/3/2005<br>wwang : 1/5/2005<br>carol : 8/11/2004<br>tkritzer : 6/2/2004<br>carol : 6/2/2004<br>tkritzer : 6/1/2004<br>terry : 5/5/2004<br>ckniffin : 4/30/2004<br>carol : 4/29/2004<br>carol : 4/29/2004<br>ckniffin : 4/29/2004<br>ckniffin : 4/12/2004<br>terry : 3/30/2004<br>tkritzer : 3/17/2004<br>tkritzer : 3/16/2004<br>terry : 3/15/2004<br>mgross : 2/16/2004<br>mgross : 2/16/2004<br>mcapotos : 9/21/2001<br>mcapotos : 9/20/2001<br>terry : 9/20/2001<br>mcapotos : 3/15/2001<br>mcapotos : 3/12/2001<br>alopez : 10/31/2000<br>terry : 10/27/2000<br>alopez : 7/10/2000<br>alopez : 6/5/2000<br>carol : 6/5/1998<br>terry : 6/5/1998<br>alopez : 5/8/1998<br>joanna : 5/8/1998<br>joanna : 12/11/1997<br>jenny : 8/22/1997<br>terry : 8/20/1997<br>terry : 6/25/1996<br>mark : 6/13/1996<br>terry : 6/13/1996<br>mark : 6/12/1996<br>terry : 6/12/1996<br>terry : 6/12/1996<br>mark : 5/31/1996<br>mark : 5/30/1996
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<strong>*</strong> 601284
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ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
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ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 1; ACVRLK1<br />
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ACTIVIN RECEPTOR-LIKE KINASE 1; ALK1
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<strong><em>HGNC Approved Gene Symbol: ACVRL1</em></strong>
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Cytogenetic location: 12q13.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:51,906,944-51,923,361 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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12q13.13
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Telangiectasia, hereditary hemorrhagic, type 2
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600376
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Activin A receptor, type II-like 1 (also called activin receptor-like kinase-1), is a type I cell-surface receptor for the TGF-beta superfamily of ligands (see TGFB1; 190180). It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail (ten Dijke et al., 1994). </p>
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<strong>Cloning and Expression</strong>
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<p>Using a PCR-based strategy based on the human activin receptor type II (see 102581) and C. elegans Daf1 (125240) gene products, ten Dijke et al. (1993) identified 4 human cDNA clones encoding putative transmembrane protein serine/threonine kinases, which they denoted activin receptor-like kinases ALK1, ALK2 (102576), ALK3 (601299), and ALK4 (601300). The ALK1 gene encodes a 503-amino acid polypeptide that shares similar domain structures with the other 3 ALK genes they cloned, including hydrophilic cysteine-rich ligand-binding domains, single hydrophobic transmembrane regions, and C-terminal intracellular portions that consist almost entirely of serine/threonine kinase domains. The ALK proteins share approximately 40% sequence identity with activin receptors type II and IIB, TGF-beta receptor (see 190181), and Daf1 in their kinase domains, but share 60 to 79% sequence identity among themselves, suggesting to ten Dijke et al. (1993) that the ALK gene products form a subfamily of receptor ser/thr kinases. By Northern blot analysis, ten Dijke et al. (1993) showed that ALK1 is most highly expressed in human placenta and lung. </p><p>Attisano et al. (1993) likewise cloned a human cDNA encoding ACVRL1 (termed TSR1 by them) and presented similar tissue localization data. They further characterized the gene product and concluded that the ACVRL1 type I cell surface receptor is a transmembrane protein kinase that associates with type II receptors to generate diverse heteromeric ser/thr kinase complexes of different signaling capacities. </p>
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<strong>Gene Structure</strong>
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<p>Berg et al. (1997) demonstrated that the coding region of the ALK1 gene is contained within 9 exons, spanning more than 15 kb of genomic DNA. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By somatic cell hybrid mapping, Roijer et al. (1998) mapped the ACVRL1 gene to chromosome 12. By fluorescence in situ hybridization, they localized the gene to 12q13. </p>
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<strong>Gene Function</strong>
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<p>Johnson et al. (1996) noted that the high expression of ALK1 in endothelial cells and other highly vascularized tissues such as lung and placenta and its low expression in other cells and tissues parallels that of endoglin (131195), which is defective in hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300), also called Osler-Rendu-Weber disease (ORW1). Endoglin is a homodimeric endothelial cell membrane protein that binds TGF-beta. ALK1 is a type I receptor which can bind TGF-beta or activin (147290) when coexpressed with the corresponding activin type II receptor (102581). They also presented a model for TGF-beta receptor functions involved in Osler-Rendu-Weber disease. They suggested that endoglin sequesters TGF-beta and presents the ligand to the signaling complex of ALK1 and a type II receptor. Presumably endoglin and ALK1 cause ORW1 by disruption of this receptor complex involved in TGF-beta signal transduction. They stated that defects in a type II receptor within this complex might also be expected to cause the phenotype of ORW1. </p><p>In COS-1 transfected cells, Abdalla et al. (2000) determined that ALK1 was found in TGFB1 and -B3 (190230) receptor complexes in association with endoglin and TGFBR2 (190182), but not in activin receptor complexes containing endoglin. In human umbilical vein endothelial cells (HUVEC), ALK1 was not detectable in TGFB1 or -B3 receptor complexes. However, in the absence of ligand, ALK1 and endoglin interactions were observed by immunoprecipitation/Western blot in HUVEC from normal as well as HHT1 and HHT2 patients. The authors hypothesized that a transient association between ALK1 and endoglin is required at a critical level to ensure vessel wall integrity. </p><p>Hereditary hemorrhagic telangiectasia and cerebral cavernous malformations (see 116860) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to Marchuk et al. (2003) that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, ALK1, KRIT1 (604214), and endoglin, in the genetic control of angiogenesis. </p><p>By yeast 2-hybrid analysis and coimmunoprecipitation experiments, Lux et al. (2005) determined that 2 proteins encoded by the PEG10 gene (609810), PEG10-RF1 and PEG10-RF1/RF2, interacted with the cytoplasmic domain of ALK1. Immunoprecipitation analysis detected interaction between PEG10-RF1 and several other members of the TGF-beta receptor family following cotransfection in COS-1 cells, but only ALK1 showed high specific interaction with PEG10-RF1. Following expression in a mink lung cell line, PEG10-RF1 inhibited signaling through ALK1. Overexpression of either ALK1 or PEG10-RF1 alone in several mammalian cell lines did not alter cell morphology, but cotransfection led to colocalization of ALK1 and PEG10-RF1 along several intracellular structures and cellular changes leading to neuron-like morphology, including dendrite-like contacts between cells. </p><p>David et al. (2007) identified BMP9 (GDF2; 605120) as a ligand for ALK1. BMP9 induced phosphorylation of SMAD1 (601595)/SMAD5 (603110)/SMAD8 (603295) in human microvascular endothelial cells via ALK1. Overexpression of the coreceptor endoglin potentiated the BMP9 response. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Hereditary Hemorrhagic Telangiectasia Type 2</em></strong></p><p>
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In affected patients from 3 families with hereditary hemorrhagic telangiectasia-2 (HHT2; 600376), Johnson et al. (1996) identified mutations in the ALK1 gene (601284.0001-601284.0003). </p><p>In 6 of 6 families with HHT in which either linkage to 12q13 was demonstrated or linkage to 9q33 had been excluded Berg et al. (1997) identified mutations in the ALK1 gene (see, e.g., 601284.0004). Mutations were also found in 3 of 6 patients from families in which available linkage data were insufficient to allow certainty with regard to the locus involved. In 2 cases in which premature termination codons were found in genomic DNA, the mutant mRNA was either not present or present at barely detectable levels, suggesting that mutations in ALK1 are functionally null alleles and probably rule out a dominant-negative effect as the pathogenetic mechanism of HHT2. Berg et al. (1997) discussed the possibility of a second hit, according to the Knudson model for tumor suppressor genes, in the pathogenesis of the local lesions. The slow enlargement of lesions suggested that if ALK1 requires a somatic second mutation for vascular lesion formation, then it is not acting as a tumor suppressor gene. Since TGF-beta signaling in endothelial cells modulates vascular remodeling by inducing changes in the extracellular matrix, complete loss of ALK1 signaling may induce remodeling of the vascular bed, rather than directly affecting the rate of endothelial cell proliferation. </p><p>In families with HHT2, Abdalla et al. (2000) reported 3 additional ALK1 missense mutations, one of which led to a G48E/A49P (601284.0005) substitution. Using a polyclonal antibody to ALK1, Abdalla et al. (2000) measured ALK1 expression on HUVEC of newborns from HHT2 families. ALK1 levels were specifically reduced in 3 HUVEC samples with ALK1 missense mutant codons, and normal in 2 newborns not carrying the mutations. Levels were normal in a HUVEC sample with deletion of S232 in the ATP binding site of ALK1. The authors concluded that HHT2 can be associated either with reduction in protein level or protein activity. </p><p>Kjeldsen et al. (2001) used denaturing gradient gel electrophoresis (DGGE) to identify mutations in the ALK1 gene in 2 families with hereditary hemorrhagic telangiectasia. In a family with an ile398-to-asn mutation (I398N; 601284.0006) there was a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding, whereas in a family with an arg374-to-thr mutation (R374T; 601284.0007), no individuals had pulmonary arteriovenous malformations and only 1 patient had a history of severe gastrointestinal bleeding. </p><p>Olivieri et al. (2002) analyzed exons 3, 7, and 8 of the ACVRL1 gene in 52 Italian probands with HHT and identified heterozygosity for 13 different mutations in 16 of the probands, including an R67W substitution (601284.0017) in 2 probands. The authors noted that a different mutation involving the same residue, an R67Q substitution, previously had been reported in an HHT patient by Berg et al. (1997). </p><p>In affected members of 16 families with HHT2, Abdalla et al. (2003) identified 14 ALK1 mutations, including 9 that were novel. This brought to 36 the number of ALK1 mutations associated with HHT2. The mutations showed clustering in exons 8 and 3, followed in frequency in exons 4 and 7. After generating a model based on the homologous ALK5 kinase domain, Abdalla et al. (2003) concluded that the 11 missense mutations modify conserved residues by altering polarity, charge, hydrophobicity, and/or size, thereby leading to misfolded and nonfunctional proteins. </p><p>In 8 unrelated probands with HHT and HHT-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified 7 ALK1 mutations (see, e.g., 601284.0001; 601284.0007; 601284.0011-601284.0013), 3 of which were novel, clustered in exons 5 to 10. Normally membrane bound, most of the ALK1 mutant proteins remained in the endoplasmic reticulum. The authors concluded that pulmonary arterial hypertension is an important disease complication of HHT, most commonly associated with ALK1 receptor signaling defects with frequent mutations in exon 8. One patient reported by Harrison et al. (2003) who had primary pulmonary hypertension without known features of HHT2 had a mutation in the GS region of the ACVRL1 protein. The patient had died, and retrospective analysis confirmed the diagnosis of primary pulmonary hypertension. Parents or surviving relatives were not available for study. Harrison et al. (2003) noted that no disease-related mutations of the GS region had previously been reported. </p><p>Loscalzo (2001) reviewed, with a hypothetical model, the role of mutations in the BMPR2 (600799) and ALK1 genes in the development of primary pulmonary hypertension. </p><p>In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding sequences of the ENG (131195) and ALK1 genes. Germline mutations were identified in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in ALK1. Lesca et al. (2004) noted that a 1-bp insertion (601284.0014) previously identified by Abdalla et al. (2003), was found in 17 unrelated patients who shared a common haplotype and were from the same region of France as the patients reported by Abdalla et al. (2003), strongly suggesting a founder effect. In 1, 2, and 7 patients, Lesca et al. (2004) identified 3 missense mutations involving codon arg411: R411Q (601284.0001), R411P (601284.0015), and R411W (601284.0009), respectively. Haplotype analysis favored both a founder effect and a mutation hotspot. </p><p>Abdalla and Letarte (2006) tabulated the known ALK1 mutations causing HHT. </p><p>Bayrak-Toydemir et al. (2006) identified mutations in 26 (76%) of 34 kindreds with HHT. Fourteen (54%) mutations were in the ENG gene, consistent with HHT1, and 12 (46%) were in the ACVRL1 gene, consistent with HHT2. </p><p>Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. A review of all mutations reported to date in the ACVRL1 gene showed that approximately 64% were in exons 3, 7, and 8. Analysis of genotype/phenotype correlations was consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations. </p><p>To explore the mechanism underlying the effect of HHT-related ALK1 mutations on receptor activity, Gu et al. (2006) generated 11 such mutants and investigated their signaling activities using reporter assay in mammalian cells and examined their effect on zebrafish embryogenesis. They showed that some of HHT2-related mutations generated a dominant-negative effect where the others gave rise to a null phenotype via loss of protein expression or receptor activity. These data indicated that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. </p><p>Olivieri et al. (2007) identified 50 different mutations in the ACVRL1 gene in 72 of 101 Italian patients with HHT. Twenty-six different ENG mutations were identified in 29 of the 101 patients. The findings were consistent with a higher frequency of ACVRL1 mutations compared to ENG mutations in HHT patients of Mediterranean ancestry. </p><p>In 4 of 45 probands with clinical HHT and negative results on direct sequencing, Shoukier et al. (2008) identified 4 different large heterozygous deletions involving the ACVRL1 gene using quantitative real-time polymerase chain reaction (qRT-PCR). The results were confirmed by multiplex ligation-dependent probe amplification (MLPA). Affected members of 2 families had deletion of the entire ACVRL1 gene. One of these deletions spanned at least 216 kb and included 5 neighboring genes, including ACVR1B, GRASP (612027), and NR4A1 (139139). The proband who carried this large deletion had no additional symptoms besides HHT, indicating that heterozygous loss of these genes has no obvious phenotypic effect. </p><p>In cellular expression studies, Ricard et al. (2010) found that none of 15 different pathogenic ALK1 mutants responded to stimulation with BMP9, as measure by phosphorylation of SMAD1 and SMAD5. Eleven mutations affecting the intracellular kinase domain of ALK1 were properly expressed at the cell surface and were able to bind BMP9. Three mutations located in the extracellular domain of ALK1 did not bind BMP9. None of the ALK1 mutants showed a dominant-negative effect on wildtype ALK1, indicating that they result in functional haploinsufficiency. Ricard et al. (2010) suggested that functional analysis of BMP9 responses can be used as a diagnostic tool to evaluate ALK1 variants. </p><p>Using whole-genome sequencing of 35 patients with HHT among 13 families and next-generation sequencing of a custom panel of genes that had been associated with HHT among 87 unrelated patients with suspected HHT, Wooderchak-Donahue et al. (2018) identified 8 patients with novel noncoding heterozygous ACVRL1 gene variants that disrupt splicing. In 1 family, an affected mother and son had an ACVRL1 intron 9:chromosome 3 translocation, t(12,3)(q13,p21), the first reported translocation to cause HHT. In the other 7 families, the variants were located within an approximately 300-bp CT-rich hotspot region of intron 9 (see, e.g., 601284.0016) that disrupted splicing. </p><p><strong><em>Somatic Mutation</em></strong></p><p>
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By SSCP analysis, D'Abronzo et al. (1999) examined 2 intracellular regions required for type I receptor signaling by human ALK1-5 type I receptors as well as the entire coding region of 2 activin type II receptors and the TGF-beta type II receptor (190182) in 64 human pituitary tumors. One patient with a gonadotroph tumor had a confirmed germline mutation in the ALK1 gene within kinase subdomains X-XI. The authors concluded that somatic mutations within these intracellular kinase regions of type I/type II receptors are rare in human pituitary tumors. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>The mature circulatory system is composed of 2 parallel, yet distinct, vascular networks that carry blood to and from the heart. Studies had suggested that endothelial tubes are specified as arteries or veins at the earliest stages of angiogenesis, before the onset of circulation. To understand the molecular basis for arterial-venous identity, Urness et al. (2000) focused on HHT, wherein arterial and venous beds fail to remain distinct. At the earliest stage of vascular development, mice lacking Acvrl1 developed large shunts between arteries and veins, downregulated arterial Efnb2 (600527), and failed to confine intravascular hematopoiesis to arteries. These mice died by midgestation with severe arteriovenous malformations resulting from fusion of major arteries and veins. The observations indicated that Acvrl1 is required for developing distinct arterial and venous vascular beds. </p><p>Srinivasan et al. (2003) created mice heterozygous for a loss-of-function mutation in Acvrl1. The mice developed age-dependent vascular lesions in the skin, extremities, oral cavity, and internal organs (lung, liver, intestine, spleen, and brain), as well as occult gastrointestinal bleeding. Major histopathologic features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage, and fibrosis. An Acvrl1 +/- mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. </p><p>Using a novel Alk1 null mutant mouse line in which a beta-galactosidase (see 230500) reporter gene (lacZ) was inserted into the Alk1 locus, Seki et al. (2003) showed that Alk1 was predominantly expressed in developing arterial, but not venous, endothelium. Alk1 expression was greatly diminished in adult arteries, but was induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis, and in existing arteries in areas of increased blood flow. This suggested a role of Alk1 signaling in arterialization and remodeling of arteries. Seki et al. (2003) concluded that, contrary to the view of HHT as a venous disease, their findings suggested that arterioles rather than venules are the primary vessels affected by the loss of an ALK1 allele. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>17 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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</span>
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<div>
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<span class="mim-text-font">
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ACVRL1, ARG411GLN
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<br />
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SNP: rs121909284,
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gnomAD: rs121909284,
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ClinVar: RCV000008726, RCV000008727, RCV000522363, RCV002371767
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</span>
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<span class="mim-text-font">
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<p>In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 1232G-A transition in the ACVRL1 gene that was predicted to result in an arg411-to-gln (R411Q) substitution. </p><p>In a French patient with HHT2, Lesca et al. (2004) identified the R411Q mutation. </p><p>In a 26-year-old woman with familial hereditary hemorrhagic telangiectasia-related primary pulmonary hypertension (see 600376), Harrison et al. (2003) identified the R411Q mutation. </p>
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</span>
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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">
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<strong>.0002 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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ACVRL1, MET376ARG
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<br />
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SNP: rs28936399,
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ClinVar: RCV000008728, RCV002444423
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 1127T-G transversion in the ALK1 gene that was predicted to cause a met376-to-arg (M376R) substitution. </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">
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<strong>.0003 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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ACVRL1, 3-BP DEL, 696CCT
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<br />
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SNP: rs387906391,
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ClinVar: RCV000230219, RCV000506933, RCV001507805, RCV002372240
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 3-bp deletion (their cDNA nucleotides 696-698) in the ALK1 gene, resulting in deletion of 1 of 2 adjacent serine residues that are conserved in most of the type I TGF-beta receptor family members from mammals to Drosophila. The deletion occurred in the kinase subdomain II. Johnson et al. (1996) also identified this deletion in a few unaffected individuals, all of whom showed the disease haplotype throughout the entire candidate interval; they were presumed to be nonpenetrant for HHT. </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">
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<strong>.0004 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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ACVRL1, TRP150CYS
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<br />
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SNP: rs121909285,
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ClinVar: RCV000008730, RCV001557555, RCV002390097
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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 a patient with hereditary hemorrhagic telangiectasia (HHT2; 600376), Berg et al. (1997) identified a G-to-T transversion in the ALK1 gene, resulting in a trp150-to-cys (W150C) substitution in the extracellular domain of the protein. </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">
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<strong>.0005 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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ACVRL1, GLY48GLU AND ALA49PRO
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<br />
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SNP: rs267606632, rs267606633, rs387906392,
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gnomAD: rs267606633,
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ClinVar: RCV000008731, RCV000144433, RCV000144434, RCV002390302
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Abdalla et al. (2000) identified a complex mutation in exon 3 of the ALK1 gene, consisting of a G143A transition, deletion of G145, and insertion of T147. The mutation converts adjacent amino acids glycine48 to glutamic acid (G48E) and alanine49 to proline (A49P) in the extracellular domain of the protein. </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">
|
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<strong>.0006 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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ACVRL1, ILE398ASN
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<br />
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SNP: rs121909286,
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ClinVar: RCV000008732
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Kjeldsen et al. (2001) identified an 1193T-A transversion in exon 8 of the ALK1 gene, resulting in an ile398-to-asn (I398N) substitution. Affected members had a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding. </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">
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<strong>.0007 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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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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ACVRL1, ARG374TRP
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<br />
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SNP: rs28936401,
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gnomAD: rs28936401,
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ClinVar: RCV000008733, RCV000008734, RCV000330901, RCV002433448, RCV004547469
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Kjeldsen et al. (2001) identified an 1120C-T transition in exon 8 of the ALK1 gene, resulting in an arg374-to-trp (R374W) substitution. No affected patients had pulmonary arteriovenous malformations, and only 1 patient had a history of severe gastrointestinal bleeding. </p><p>In a population-based study of primarily French HHT2 patients, Lesca et al. (2008) showed that the R374W mutation associated with a shared ancestral haplotype in a subset of patients, suggesting a founder effect with the mutation arising approximately 300 years ago. In other patients, the mutation was related to different independent mutation events. </p><p>In a 41-year-old woman with hereditary hemorrhagic telangiectasis-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified the R374W mutation. The patient had an atrial septal defect repaired before the onset of significantly raised pulmonary artery pressure, and also had a sib with primary pulmonary hypertension (see 178600). </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">
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<strong>.0008 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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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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ACVRL1, 3-BP DEL, 759GAC
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<br />
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SNP: rs387906393,
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ClinVar: RCV000008735, RCV000008736, RCV000755791, RCV002390098
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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 affected members of a family with hereditary hemorrhagic telangiectasia-2 (HHT2; 600376), Trembath et al. (2001) identified a 3-bp deletion (del759-761) in exon 6 of the ACVRL1 gene, resulting in deletion of asp254. Three members had isolated HHT and 2 members had both HHT and pulmonary arterial hypertension, 1 of whom had pulmonary arteriovenous malformations. </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>.0009 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
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</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
|
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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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ACVRL1, ARG411TRP
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<br />
|
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|
|
SNP: rs121909287,
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ClinVar: RCV000008737, RCV000008738, RCV000199381, RCV002362571
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg411-to-trp (R411W) mutation in exon 8 of the ACVRL1 gene. One patient had HHT and pulmonary arterial hypertension (see 600376). </p><p>In 7 unrelated French patients with HHT2, Lesca et al. (2004) identified the R411W mutation. </p><p>In a population-based study of primarily French HHT2 patients, Lesca et al. (2008) showed that the R411W mutation associated with a shared ancestral haplotype in a subset of patients, suggesting a founder effect with the mutation arising approximately 300 years ago. In other patients, the mutation was related to different independent mutation events. </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">
|
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<strong>.0010 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</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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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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ACVRL1, ARG484TRP
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<br />
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SNP: rs121909288,
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gnomAD: rs121909288,
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ClinVar: RCV000008739, RCV000008740, RCV000507762, RCV001003756, RCV001564363, RCV002390099
|
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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 affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Trembath et al. (2001) identified an arg484-to-trp (R484W) mutation in exon 10 of the ACVRL1 gene. Two patients had isolated HHT, 2 had isolated pulmonary arterial hypertension, and 1 had both HHT and pulmonary hypertension (see 600376). Trembath et al. (2001) noted that the arginine residue at this position is conserved in mouse and human ACVRL1 and in several human paralogs. </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>.0011 PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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ACVRL1, GLY211ASP
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<br />
|
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|
|
SNP: rs28936687,
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|
|
ClinVar: RCV000008741, RCV001001392
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 56-year-old woman with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified a 632G-A transition in exon 6 of the ACVRL1 gene, resulting in a gly211-to-asp (G211D) substitution. The patient had a 6-month exposure to an appetite suppressant, at least 8 years before the onset of symptoms. </p>
|
|
</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>.0012 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, CYS344TYR
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|
|
<br />
|
|
|
|
SNP: rs28936688,
|
|
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|
|
|
|
ClinVar: RCV000008742, RCV000008743, RCV001507809, RCV001844010, RCV002381244
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified a 1031G-A transition in exon 7 of the ACVRL1 gene, resulting in a cys344-to-tyr (C344Y) substitution. This mutation had been reported previously by Abdalla et al. (2000) in patients with isolated hereditary hemorrhagic telangiectasia (HHT2; 600376). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, TRP399SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909289,
|
|
|
|
|
|
|
|
ClinVar: RCV000008744, RCV002345234, RCV005089210
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 29-year-old woman with hereditary hemorrhagic telangiectasia-related pulmonary arterial hypertension (see 600376), Harrison et al. (2003) identified a 1196G-C transversion in exon 8 of the ACVRL1 gene, resulting in a trp399-to-ser (W399S) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, 1-BP INS, 1113G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906394,
|
|
|
|
|
|
|
|
ClinVar: RCV000008745
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with hereditary hemorrhagic telangiectasia-2 (HHT2; 600376), Abdalla et al. (2003) identified a 1-bp insertion in exon 8 of the ACVRL1 gene, 1113insG, resulting in a frameshift at codon 371 and the addition of 51 novel amino acids. </p><p>In 17 of 160 unrelated patients with HHT2, Lesca et al. (2004) identified the 1113insG mutation, which they referred to as a 1-bp duplication (1112dupG). The 17 patients shared a common haplotype and all originated from the Rhone-Alpes region of France, strongly suggesting a founder effect. Lesca et al. (2004) stated that the family reported by Abdalla et al. (2003) originated from the same region. </p><p>Lesca et al. (2008) identified the 1-bp insertion (1113insG), which they called 1112dupG, in the ACVRL1 gene as the most common mutation responsible for HHT2 (600376) in 35 of 96 French and Italian probands with the disorder. Haplotype analysis indicated a founder effect, estimated to have occurred about 325 years ago in an inhabitant of the Haut-Jura mountains. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, ARG411PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909284,
|
|
|
|
|
|
gnomAD: rs121909284,
|
|
|
|
|
|
ClinVar: RCV000008746
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated French patients with hereditary hemorrhagic telangiectasia-2 (HHT2; 600376), Lesca et al. (2004) identified a 1232G-C transversion in exon 8 of the ACVRL1 gene, resulting in an arg411-to-pro (R411P) mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, IVS9AS, C-G, -216
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111710113,
|
|
|
|
|
|
gnomAD: rs111710113,
|
|
|
|
|
|
ClinVar: RCV000754826
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-generation family (family 1) with hereditary hemorrhagic telangiectasia-2 (HHT2; 600376), Wooderchak-Donahue et al. (2018) identified a novel heterozygous deep intronic variant (c.1378-216C-G) in the ACVRL1 gene. The mutation, which was identified by whole-genome sequencing and confirmed by Sanger sequencing, was predicted by splice site prediction programs to create a new splice acceptor site and alter splicing. RNA studies confirmed partial retention of intron 9 in the aberrantly spliced product. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACVRL1, ARG67TRP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV004794710
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 apparently unrelated Italian probands (MC and P301) with hereditary hemorrhagic telangiectasia (HHT2; 600376), Olivieri et al. (2002) identified heterozygosity for a c.199C-T transversion in exon 3 of the ACVRL1 gene, resulting in an arg67-to-trp (R67W) substitution at a conserved residue. The proband P301 was a member of the large Italian family originally studied by Piantanida et al. (1996); no relationship could be found between the 2 families up to the great-grandparents, but the authors noted that both family names originated from closely related geographical areas in northern Italy. Because the probands also shared alleles at the ACVRL1 intronic D12S167 polymorphism and at the common exon 3 polymorphism (cp3), the authors concluded that a common ancestor was very likely. Extensive liver involvement in the large family was confirmed, and intrahepatic arteriovenous shunts were also present in the other family sharing the same mutation. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<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>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
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<li>
|
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<p class="mim-text-font">
|
|
Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M.
|
|
<strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong>
|
|
Europ. J. Hum. Genet. 11: 279-287, 2003.
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|
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|
[PubMed: 12700602]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200919]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Abdalla, S. A., Letarte, M.
|
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<strong>Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.</strong>
|
|
J. Med. Genet. 43: 97-110, 2006.
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|
|
[PubMed: 15879500]
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[Full Text: https://doi.org/10.1136/jmg.2005.030833]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M.
|
|
<strong>Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.</strong>
|
|
Hum. Molec. Genet. 9: 1227-1237, 2000.
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|
|
[PubMed: 10767348]
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[Full Text: https://doi.org/10.1093/hmg/9.8.1227]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Attisano, L., Carcamo, J., Ventura, F., Weis, F. M. B., Massague, J., Wrana, J. L.
|
|
<strong>Identification of human activin and TGF-beta type I receptors that form heteromeric kinase complexes with type II receptors.</strong>
|
|
Cell 75: 671-680, 1993.
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|
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|
|
[PubMed: 8242742]
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|
[Full Text: https://doi.org/10.1016/0092-8674(93)90488-c]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.-S., Gedge, F., Tang, W., Coon, H., Mao, R.
|
|
<strong>Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.</strong>
|
|
Am. J. Med. Genet. 140A: 463-470, 2006.
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|
[PubMed: 16470787]
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[Full Text: https://doi.org/10.1002/ajmg.a.31101]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A.
|
|
<strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong>
|
|
Am. J. Hum. Genet. 61: 60-67, 1997.
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|
[PubMed: 9245985]
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[Full Text: https://doi.org/10.1086/513903]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
D'Abronzo, F. H., Swearingen, B., Klibanski, A., Alexander, J. M.
|
|
<strong>Mutational analysis of activin/transforming growth factor-beta type I and type II receptor kinases in human pituitary tumors.</strong>
|
|
J. Clin. Endocr. Metab. 84: 1716-1721, 1999.
|
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|
[PubMed: 10323406]
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|
[Full Text: https://doi.org/10.1210/jcem.84.5.5704]
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</p>
|
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</li>
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<li>
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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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Marla J. F. O'Neill - updated : 11/22/2024<br>Sonja A. Rasmussen - updated : 02/05/2019<br>Cassandra L. Kniffin - updated : 6/13/2011<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Cassandra L. Kniffin - updated : 9/5/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Victor A. McKusick - updated : 6/8/2006<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Victor A. McKusick - updated : 3/9/2006<br>Patricia A. Hartz - updated : 1/25/2006<br>George E. Tiller - updated : 3/3/2005<br>George E. Tiller - updated : 1/5/2005<br>Victor A. McKusick - updated : 5/5/2004<br>Cassandra L. Kniffin - reorganized : 4/29/2004<br>Cassandra L. Kniffin - updated : 4/12/2004<br>Natalie E. Krasikov - updated : 3/30/2004<br>Marla J. F. O'Neill - updated : 3/15/2004<br>Victor A. McKusick - updated : 9/20/2001<br>Sonja A. Rasmussen - updated : 3/12/2001<br>Victor A. McKusick - updated : 10/27/2000<br>George E. Tiller - updated : 7/10/2000<br>John A. Phillips, III - updated : 6/5/2000<br>Alan F. Scott - updated : 6/5/1998<br>Victor A. McKusick - updated : 8/20/1997<br>Mark H. Paalman - updated : 6/13/1996
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Victor A. McKusick : 5/29/1996
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alopez : 11/22/2024<br>carol : 02/24/2020<br>carol : 08/22/2019<br>carol : 02/06/2019<br>carol : 02/05/2019<br>carol : 12/07/2017<br>carol : 12/06/2017<br>carol : 09/16/2016<br>terry : 08/17/2012<br>wwang : 6/24/2011<br>ckniffin : 6/13/2011<br>wwang : 9/24/2008<br>ckniffin : 9/16/2008<br>wwang : 9/9/2008<br>ckniffin : 9/5/2008<br>wwang : 3/19/2008<br>ckniffin : 2/29/2008<br>wwang : 4/4/2007<br>alopez : 6/9/2006<br>terry : 6/8/2006<br>wwang : 5/3/2006<br>ckniffin : 4/27/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>alopez : 3/14/2006<br>terry : 3/9/2006<br>mgross : 1/25/2006<br>alopez : 3/3/2005<br>wwang : 1/5/2005<br>carol : 8/11/2004<br>tkritzer : 6/2/2004<br>carol : 6/2/2004<br>tkritzer : 6/1/2004<br>terry : 5/5/2004<br>ckniffin : 4/30/2004<br>carol : 4/29/2004<br>carol : 4/29/2004<br>ckniffin : 4/29/2004<br>ckniffin : 4/12/2004<br>terry : 3/30/2004<br>tkritzer : 3/17/2004<br>tkritzer : 3/16/2004<br>terry : 3/15/2004<br>mgross : 2/16/2004<br>mgross : 2/16/2004<br>mcapotos : 9/21/2001<br>mcapotos : 9/20/2001<br>terry : 9/20/2001<br>mcapotos : 3/15/2001<br>mcapotos : 3/12/2001<br>alopez : 10/31/2000<br>terry : 10/27/2000<br>alopez : 7/10/2000<br>alopez : 6/5/2000<br>carol : 6/5/1998<br>terry : 6/5/1998<br>alopez : 5/8/1998<br>joanna : 5/8/1998<br>joanna : 12/11/1997<br>jenny : 8/22/1997<br>terry : 8/20/1997<br>terry : 6/25/1996<br>mark : 6/13/1996<br>terry : 6/13/1996<br>mark : 6/12/1996<br>terry : 6/12/1996<br>terry : 6/12/1996<br>mark : 5/31/1996<br>mark : 5/30/1996
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