4187 lines
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Entry
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- *157147 - MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; MTTP
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- OMIM
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<p>
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<span class="h4">*157147</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<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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<a href="#description">Description</a>
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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="#geneFamily">Gene Family</a>
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<a href="#mapping">Mapping</a>
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<a href="#biochemicalFeatures">Biochemical Features</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/157147">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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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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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 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 id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="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=ENSG00000138823;t=ENST00000265517" 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=4547" 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=157147" 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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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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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=ENSG00000138823;t=ENST00000265517" 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_000253,NM_001300785,NM_001386140" 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_001386140" 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=157147" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01144&isoform_id=01144_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/MTTP" 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/414669,469096,1217639,1709167,1834501,4261846,4262813,38540933,115528724,115528911,119626511,153285408,158255022,221044164,1887447763,1888350701" 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/P55157" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4547" 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=ENSG00000138823;t=ENST00000265517" 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=MTTP" 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=MTTP" 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+4547" 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/MTTP" 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:4547" 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/4547" 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=chr4&hgg_gene=ENST00000265517.10&hgg_start=99564130&hgg_end=99623997&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 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:7467" 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://medlineplus.gov/genetics/gene/mttp" 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=157147[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=157147[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/ENSG00000138823" 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=MTTP" 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=MTTP" 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=MTTP" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MTTP&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/PA164742099" 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:7467" 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/FBgn0266369.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:106926" 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/MTTP#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:106926" 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/4547/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=4547" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001099;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040419-2" 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:4547" 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=MTTP&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 190787008<br />
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<strong>ICD10CM:</strong> E78.6<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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157147
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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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MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; MTTP
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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>
|
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<span class="mim-font">
|
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MTP<br />
|
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MTP, LARGE SUBUNIT
|
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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=MTTP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MTTP</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/4/435?start=-3&limit=10&highlight=435">4q23</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:99564130-99623997&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'})">4:99,564,130-99,623,997</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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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>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<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>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/435?start=-3&limit=10&highlight=435">
|
|
4q23
|
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</a>
|
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</span>
|
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</td>
|
|
|
|
|
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<td>
|
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<span class="mim-font">
|
|
Abetalipoproteinemia
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/200100"> 200100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/157147" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/157147" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
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<p>Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. It is a heterodimer composed of a 55-kD multifunctional protein, protein disulfide isomerase (P4HB; <a href="/entry/176790">176790</a>), and a unique large subunit with an apparent molecular weight of 88 kD (<a href="#20" class="mim-tip-reference" title="Wetterau, J. R., Combs, K. A., Spinner, S. N., Joiner, B. J. <strong>Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex.</strong> J. Biol. Chem. 265: 9800-9807, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2351674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2351674</a>]" pmid="2351674">Wetterau et al., 1990</a>). MTP was isolated as a soluble protein from the lumen of a microsomal fraction of liver and intestine. (<a href="#13" class="mim-tip-reference" title="Rehberg, E. F., Samson-Bouma, M.-E., Kienzle, B., Blinderman, L., Jamil, H., Wetterau, J. R., Aggerbeck, L. P., Gordon, D. A. <strong>A novel abetalipoproteinemia genotype: identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.</strong> J. Biol. Chem. 271: 29945-29952, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939939</a>] [<a href="https://doi.org/10.1074/jbc.271.47.29945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939939">Rehberg et al. (1996)</a> referred to the large subunit as the 97-kD subunit.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2351674+8939939" 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="#15" class="mim-tip-reference" title="Sharp, D., Blinderman, L., Combs, K. A., Kienzle, B., Ricci, B., Wager-Smith, K., Gil, C. M., Turck, C. W., Bouma, M.-E., Rader, D. J., Aggerbeck, L. P., Gregg, R. E., Gordon, D. A., Wetterau, J. R. <strong>Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.</strong> Nature 365: 65-69, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8361539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8361539</a>] [<a href="https://doi.org/10.1038/365065a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8361539">Sharp et al. (1993)</a> isolated and sequenced cDNA encoding the large subunit of MTP. A comparison of the normal sequence with the genomic sequences from 2 abetalipoproteinemic subjects demonstrated a homozygous frameshift mutation in one and a homozygous nonsense mutation in the other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8361539" 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="Nakamuta, M., Chang, B. H.-J., Hoogeveen, R., Li, W.-H., Chan, L. <strong>Mouse microsomal triglyceride transfer protein large subunit: cDNA cloning, tissue-specific expression, and chromosomal localization.</strong> Genomics 33: 313-316, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8660984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8660984</a>] [<a href="https://doi.org/10.1006/geno.1996.0200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8660984">Nakamuta et al. (1996)</a> cloned and sequenced mouse MTP cDNA. The DNA-deduced amino acid sequence indicated that mouse MTP contains 894 amino acids; the mouse protein showed 93, 86, and 83% sequence identity to the hamster, human, and bovine sequences, respectively. Northern blot analysis indicated that mouse MTP mRNA is expressed at high levels in the small intestine and at substantially lower levels in the liver; it was not detectable in 6 other tissues examined. The authors noted that the C-terminal region of MTP was more highly conserved than the N-terminal region in human, bovine, hamster, and mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8660984" 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 MTP gene has 17 introns (<a href="#17" class="mim-tip-reference" title="Shoulders, C. C., Narcisi, T. M. E., Read, J., Chester, S. A., Brett, D. J., Scott, J., Anderson, T. A., Levitt, D. G., Banaszak, L. J. <strong>The abetalipoproteinemia gene is a member of the vitellogenin family and encodes an alpha-helical domain. (Letter)</strong> Nature Struct. Biol. 1: 285-286, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7664034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7664034</a>] [<a href="https://doi.org/10.1038/nsb0594-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7664034">Shoulders et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7664034" 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="#17" class="mim-tip-reference" title="Shoulders, C. C., Narcisi, T. M. E., Read, J., Chester, S. A., Brett, D. J., Scott, J., Anderson, T. A., Levitt, D. G., Banaszak, L. J. <strong>The abetalipoproteinemia gene is a member of the vitellogenin family and encodes an alpha-helical domain. (Letter)</strong> Nature Struct. Biol. 1: 285-286, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7664034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7664034</a>] [<a href="https://doi.org/10.1038/nsb0594-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7664034">Shoulders et al. (1994)</a> pointed out that MTP has amino acid sequence homology with lipovitellin, a component of an ancient transport and storage lipoprotein found in egg-laying animals. Lipovitellin is derived by proteolytic cleavage of vitellogenin, which is synthesized in the liver under estrogen control, and serves as a source of lipids and amino acids during embryogenesis. <a href="#17" class="mim-tip-reference" title="Shoulders, C. C., Narcisi, T. M. E., Read, J., Chester, S. A., Brett, D. J., Scott, J., Anderson, T. A., Levitt, D. G., Banaszak, L. J. <strong>The abetalipoproteinemia gene is a member of the vitellogenin family and encodes an alpha-helical domain. (Letter)</strong> Nature Struct. Biol. 1: 285-286, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7664034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7664034</a>] [<a href="https://doi.org/10.1038/nsb0594-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7664034">Shoulders et al. (1994)</a> showed the MTP is a member of the vitellogenin gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7664034" 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 PCR analysis of rodent/human somatic cell hybrids followed by fluorescence in situ hybridization, <a href="#9" class="mim-tip-reference" title="Narcisi, T. M. E., Shoulders, C. C., Chester, S. A., Read, J., Brett, D. J., Harrison, G. B., Grantham, T. T., Fox, M. F., Povey, S., de Bruin, T. W. A., Erkelens, D. W., Muller, D. P. R., Lloyd, J. K., Scott, J. <strong>Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia.</strong> Am. J. Hum. Genet. 57: 1298-1310, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533758</a>]" pmid="8533758">Narcisi et al. (1995)</a> mapped the MTP gene to 4q22-q24. By Southern blots of interspecific backcross panels, <a href="#8" class="mim-tip-reference" title="Nakamuta, M., Chang, B. H.-J., Hoogeveen, R., Li, W.-H., Chan, L. <strong>Mouse microsomal triglyceride transfer protein large subunit: cDNA cloning, tissue-specific expression, and chromosomal localization.</strong> Genomics 33: 313-316, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8660984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8660984</a>] [<a href="https://doi.org/10.1006/geno.1996.0200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8660984">Nakamuta et al. (1996)</a> mapped the mouse Mtp gene to distal chromosome 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8533758+8660984" 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="#19" class="mim-tip-reference" title="Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., Gregg, R. E. <strong>Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.</strong> Science 258: 999-1001, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1439810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1439810</a>] [<a href="https://doi.org/10.1126/science.1439810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1439810">Wetterau et al. (1992)</a> reported that the large subunit of MTP was not detectable in 4 unrelated subjects with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>), a rare autosomal recessive disease characterized by a defect in assembly or secretion of plasma lipoproteins that contain apolipoprotein B (APOB; <a href="/entry/107730">107730</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1439810" 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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In a cohort of 8 patients with classic abetalipoproteinemia, <a href="#9" class="mim-tip-reference" title="Narcisi, T. M. E., Shoulders, C. C., Chester, S. A., Read, J., Brett, D. J., Harrison, G. B., Grantham, T. T., Fox, M. F., Povey, S., de Bruin, T. W. A., Erkelens, D. W., Muller, D. P. R., Lloyd, J. K., Scott, J. <strong>Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia.</strong> Am. J. Hum. Genet. 57: 1298-1310, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533758</a>]" pmid="8533758">Narcisi et al. (1995)</a> identified a mutation of the MTP gene in both alleles of all individuals. Each mutant allele was predicted to encode a truncated form of MTP with a variable number of aberrant amino acids at its C-terminal end. Expression of genetically engineered forms of MTP in COS-1 cells indicated to the authors that the C-terminal portion of MTP is necessary for triglyceride-transfer activity. A deletion of 20 amino acids from the carboxyl terminus of the 894-amino acid protein and a missense mutation of cys878-to-ser both abolished activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533758" 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="#6" class="mim-tip-reference" title="Heath, K. E., Luong, L.-A., Leonard, J. V., Chester, A., Shoulders, C. C., Scott, J., Middleton-Price, H. R., Humphries, S. E., Talmud, P. J. <strong>The use of a highly informative CA repeat polymorphism within the abetalipoproteinaemia locus (4q22-24).</strong> Prenatal Diag. 17: 1181-1186, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9467817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9467817</a>] [<a href="https://doi.org/10.1002/(sici)1097-0223(199712)17:12<1181::aid-pd205>3.0.co;2-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9467817">Heath et al. (1997)</a> described a highly informative CA repeat polymorphism within the MTP gene which can be used for diagnosis, including prenatal diagnosis, in lieu of a mutation search, which can be difficult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9467817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Ohashi, K., Ishibashi, S., Osuga, J., Tozawa, R., Harada, K., Yahagi, N., Shionoiri, F., Iizuka, Y., Tamura, Y., Nagai, R., Illingworth, D. R., Gotoda, T., Yamada, N. <strong>Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.</strong> J. Lipid Res. 41: 1199-1204, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946006</a>]" pmid="10946006">Ohashi et al. (2000)</a> stated that 14 separate mutations in the MTP gene and/or cDNA from patients with abetalipoproteinemia had been described. They identified MTP mutations in all 8 alleles of 2 Japanese and 2 American patients with ABL. These included a second incidence of a missense mutation (<a href="#0007">157147.0007</a>; see <a href="#0005">157147.0005</a> for the first missense mutation described). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946006" 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="Benayoun, L., Granot, E., Rizel, L., Allon-Shalev, S., Behar, D. M., Ben-Yosef, T. <strong>Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.</strong> Molec. Genet. Metab. 90: 453-457, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17275380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17275380</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17275380">Benayoun et al. (2007)</a> investigated the genetic basis for abetalipoproteinemia in a cohort of Israeli families. In Ashkenazi Jewish patients, <a href="#2" class="mim-tip-reference" title="Benayoun, L., Granot, E., Rizel, L., Allon-Shalev, S., Behar, D. M., Ben-Yosef, T. <strong>Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.</strong> Molec. Genet. Metab. 90: 453-457, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17275380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17275380</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17275380">Benayoun et al. (2007)</a> identified a conserved haplotype and a common MTP mutation, gly865 to ter (<a href="#0010">157147.0010</a>), with a carrier frequency of 1:131 in this population. They also reported the first case of abetalipoproteinemia and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 kb, including MTP and 8 other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275380" 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="#3" class="mim-tip-reference" title="Cuchel, M., Bloedon, L. T., Szapary, P. O., Kolansky, D. M., Wolfe, M. L., Sarkis, A., Millar, J. S., Ikewaki, K., Siegelman, E. S., Gregg, R. E., Rader, D. J. <strong>Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.</strong> New Eng. J. Med. 356: 148-156, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17215532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17215532</a>] [<a href="https://doi.org/10.1056/NEJMoa061189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17215532">Cuchel et al. (2007)</a> reported that inhibition of the microsomal triglyceride transfer protein reduces plasma low density lipoprotein (LDL) cholesterol in homozygous familial hypercholesterolemia (<a href="/entry/143890">143890</a>). Treatment-related hepatic steatosis was predictable from studies in animals, variable among study subjects, and reversible with discontinuation of the inhibitor. <a href="#7" class="mim-tip-reference" title="Hegele, R. A. <strong>Familial hypercholesterolemia. (Letter)</strong> New Eng. J. Med. 356: 1779 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17460234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17460234</a>] [<a href="https://doi.org/10.1056/NEJMc070300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17460234">Hegele (2007)</a> suggested that clues to the long-term consequences of inhibition of the microsomal triglyceride transfer protein might be found among patients with abetalipoproteinemia (<a href="/entry/200100">200100</a>). Cirrhosis has been reported in patients with abetalipoproteinemia (<a href="#11" class="mim-tip-reference" title="Partin, J. S., Partin, J. C., Schubert, W. K., McAdams, A. J. <strong>Liver ultrastructure in abetalipoproteinemia: evolution of micronodular cirrhosis.</strong> Gastroenterology 67: 107-118, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4135110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4135110</a>]" pmid="4135110">Partin et al., 1974</a>). Fat accumulation within enterocytes and steatorrhea are defining features of abetalipoproteinemia; ileal adenocarcinoma developed in one patient with abetalipoproteinemia who survived for a long period (<a href="#1" class="mim-tip-reference" title="Al-Shali, K., Wang, J., Rosen, F., Hegele, R. A. <strong>Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia.</strong> Clin. Genet. 63: 135-138, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630961</a>] [<a href="https://doi.org/10.1046/j.0009-9163.2002.00175.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630961">Al-Shali et al., 2003</a>). <a href="#4" class="mim-tip-reference" title="Cuchel, M., Rader, D. J. <strong>Reply to Hegele Familial hypercholesterolemia.(Letter)</strong> New Eng. J. Med. 356: 1779-1780, 2007."None>Cuchel and Rader (2007)</a> agreed with the suggestions of <a href="#7" class="mim-tip-reference" title="Hegele, R. A. <strong>Familial hypercholesterolemia. (Letter)</strong> New Eng. J. Med. 356: 1779 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17460234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17460234</a>] [<a href="https://doi.org/10.1056/NEJMc070300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17460234">Hegele (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17460234+4135110+12630961+17215532" 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>MTTP Polymorphisms</em></strong></p><p>
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In a cohort of 716 German men genotyped for the ile128-to-thr polymorphism of the MTP gene (I128T; <a href="#0009">157147.0009</a>), <a href="#14" class="mim-tip-reference" title="Rubin, D., Helwig, U., Pfeuffer, M., Schreiber, S., Boeing, H., Fisher, E., Pfeiffer, A., Freitag-Wolf, S., Foelsch, U. R., Doering, F., Schrezenmeir, J. <strong>A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.</strong> J. Hum. Genet. 51: 567-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16721486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16721486</a>] [<a href="https://doi.org/10.1007/s10038-006-0400-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16721486">Rubin et al. (2006)</a> found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (<a href="/entry/125853">125853</a>). In a case-control study of 190 patients with type 2 diabetes and 380 controls, <a href="#14" class="mim-tip-reference" title="Rubin, D., Helwig, U., Pfeuffer, M., Schreiber, S., Boeing, H., Fisher, E., Pfeiffer, A., Freitag-Wolf, S., Foelsch, U. R., Doering, F., Schrezenmeir, J. <strong>A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.</strong> J. Hum. Genet. 51: 567-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16721486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16721486</a>] [<a href="https://doi.org/10.1007/s10038-006-0400-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16721486">Rubin et al. (2006)</a> observed a significantly lower incidence of type 2 diabetes in individuals with the thr128 genotype; the authors suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16721486" 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>Although deficiency in MTP causes abetalipoproteinemia, the role of MTP in the assembly and secretion of very low density lipoprotein (VLDL) in the liver was not precisely understood. To this end, <a href="#12" class="mim-tip-reference" title="Raabe, M., Veniant, M. M., Sullivan, M. A., Zlot, C. H., Bjorkegren, J., Nielsen, L. B., Wong, J. S., Hamilton, R. L., Young, S. G. <strong>Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.</strong> J. Clin. Invest. 103: 1287-1298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10225972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10225972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10225972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10225972">Raabe et al. (1999)</a> knocked out the Mtp gene in the mouse. Achieving the objective was thwarted by a lethal embryonic phenotype. <a href="#12" class="mim-tip-reference" title="Raabe, M., Veniant, M. M., Sullivan, M. A., Zlot, C. H., Bjorkegren, J., Nielsen, L. B., Wong, J. S., Hamilton, R. L., Young, S. G. <strong>Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.</strong> J. Clin. Invest. 103: 1287-1298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10225972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10225972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10225972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10225972">Raabe et al. (1999)</a> found, however, that they could produce mice harboring a 'floxed' Mtp allele and then use Cre-mediated recombination to generate liver-specific Mtp knockout mice. Inactivation of the Mtp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and high density lipoprotein (HDL) cholesterol levels. Mtp gene inactivation lowered apoB-100 levels in the plasma by more than 95% but reduced plasma apoB-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wildtype mouse liver revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (endoplasmic reticulum (ER) and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. <a href="#12" class="mim-tip-reference" title="Raabe, M., Veniant, M. M., Sullivan, M. A., Zlot, C. H., Bjorkegren, J., Nielsen, L. B., Wong, J. S., Hamilton, R. L., Young, S. G. <strong>Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.</strong> J. Clin. Invest. 103: 1287-1298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10225972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10225972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10225972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10225972">Raabe et al. (1999)</a> concluded that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apoB-100 from the liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10225972" 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://www.ncbi.nlm.nih.gov/clinvar?term=157147[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1560614154 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560614154;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=rs1560614154" 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=rs1560614154" 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 39-year-old female with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>), the offspring of a consanguineous mating, <a href="#15" class="mim-tip-reference" title="Sharp, D., Blinderman, L., Combs, K. A., Kienzle, B., Ricci, B., Wager-Smith, K., Gil, C. M., Turck, C. W., Bouma, M.-E., Rader, D. J., Aggerbeck, L. P., Gregg, R. E., Gordon, D. A., Wetterau, J. R. <strong>Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.</strong> Nature 365: 65-69, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8361539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8361539</a>] [<a href="https://doi.org/10.1038/365065a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8361539">Sharp et al. (1993)</a> isolated total RNA and reverse transcribed it into first-strand cDNA. The cDNA encoding the large subunit of MTP was amplified by PCR and sequenced directly. Three independent PCR products revealed a cytosine deletion at base 215. The frameshift mutation led to a premature stop codon 21 bases downstream and a predicted translation product of 78 amino acids. The 187-bp exon that encoded the mutation was amplified from the subject's genomic DNA and sequenced directly. A single sequence that contained the frameshift mutation was observed, indicating that both alleles contained the defect, i.e., that the patient was homozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8361539" 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">rs199422219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422219;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=rs199422219" 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=rs199422219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#15" class="mim-tip-reference" title="Sharp, D., Blinderman, L., Combs, K. A., Kienzle, B., Ricci, B., Wager-Smith, K., Gil, C. M., Turck, C. W., Bouma, M.-E., Rader, D. J., Aggerbeck, L. P., Gregg, R. E., Gordon, D. A., Wetterau, J. R. <strong>Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.</strong> Nature 365: 65-69, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8361539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8361539</a>] [<a href="https://doi.org/10.1038/365065a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8361539">Sharp et al. (1993)</a> constructed a genomic library from the DNA of a 14-year-old abetalipoproteinemic (ABL; <a href="/entry/200100">200100</a>) female previously shown to lack MTP (<a href="#19" class="mim-tip-reference" title="Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., Gregg, R. E. <strong>Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.</strong> Science 258: 999-1001, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1439810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1439810</a>] [<a href="https://doi.org/10.1126/science.1439810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1439810">Wetterau et al., 1992</a>) and isolated clones encoding the large subunit of MTP. Sequence analysis revealed a C-to-T mutation corresponding to base 1783 of the cDNA. The mutation changed an arg codon to a premature stop codon. A truncated translation product of 594 amino acids was predicted. The nonsense mutation also eliminated a TaqI restriction endonuclease site. The normal exon encoding base 1783 was digested into 2 fragments by TaqI. DNA from the abetalipoproteinemic subject was not digested at this site, indicating that both alleles contained the defect, i.e., the subject was homozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1439810+8361539" 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 ABETALIPOPROTEINEMIA</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> rs1429774833 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1429774833;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/rs1429774833?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=rs1429774833" 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=rs1429774833" 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=RCV000015304 OR RCV003556024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015304, RCV003556024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015304...</a>
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<p>In sibs with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>) reported by <a href="#18" class="mim-tip-reference" title="Talmud, P. J., Lloyd, J. K., Muller, D. P. R., Collins, D. R., Scott, J., Humphries, S. <strong>Genetic evidence from two families that the apolipoprotein B gene is not involved in abetalipoproteinemia.</strong> J. Clin. Invest. 82: 1803-1806, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2903181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2903181</a>] [<a href="https://doi.org/10.1172/JCI113795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2903181">Talmud et al. (1988)</a>, <a href="#16" class="mim-tip-reference" title="Shoulders, C. C., Brett, D. J., Bayliss, J. D., Narcisi, T. M. E., Jarmuz, A., Grantham, T. T., Leoni, P. R. D., Bhattacharya, S., Pease, R. J., Cullen, P. M., Levi, S., Byfield, P. G. H., Purkiss, P., Scott, J. <strong>Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein.</strong> Hum. Molec. Genet. 2: 2109-2116, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111381</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111381">Shoulders et al. (1993)</a> demonstrated homozygosity for a splice mutation in the MTP protein. RT-PCR of mRNA prepared from intestinal biopsies from one of the patients provided starting material. By sequencing genomic and cDNA clones from the patient, <a href="#16" class="mim-tip-reference" title="Shoulders, C. C., Brett, D. J., Bayliss, J. D., Narcisi, T. M. E., Jarmuz, A., Grantham, T. T., Leoni, P. R. D., Bhattacharya, S., Pease, R. J., Cullen, P. M., Levi, S., Byfield, P. G. H., Purkiss, P., Scott, J. <strong>Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein.</strong> Hum. Molec. Genet. 2: 2109-2116, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111381</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111381">Shoulders et al. (1993)</a> demonstrated that the patient's cDNA contained an abnormal 91-bp sequence at the site of an intron/exon splice junction between nucleotides 1867 and 1868 encoding amino acid codon 623. The DNA sequence 3-prime of nucleotide 1867 encoded 31 amino acids before an in-frame stop codon was encountered. No abnormality of the invariant GT and AG intron/exon consensus sequences was found. Sequencing of genomic clones from each parent demonstrated a G-to-A substitution at the +5 position of the 5-prime splice site in 1 allele. All of the patient's cDNA and genomic clones bore an A at this position. Thus, the patient had an exon skip, causing a frameshift and the generation of a premature UAG stop codon at nucleotides 1869-1871 of the cDNA. The G-to-A mutation at the +5 position of a splice donor site was associated with production of 2 mRNA species: one failed to splice the intron containing the mutation, and the other skipped the exon immediately upstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2903181+8111381" 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">rs1560621444 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560621444;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=rs1560621444" 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=rs1560621444" 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=RCV000015305" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015305" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015305</a>
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<p>In a 29-year-old Japanese male with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>), <a href="#21" class="mim-tip-reference" title="Yang, X. P., Inazu, A., Yagi, K., Kajinami, K., Koizumi, J., Mabuchi, H. <strong>Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 1950-1955, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10446076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10446076</a>] [<a href="https://doi.org/10.1161/01.atv.19.8.1950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10446076">Yang et al. (1999)</a> identified a homozygous G-to-A transition at the -1 position of the intron 9 splice acceptor site of the MTP gene. This mutation alters the splicing of the mRNA, resulting in an in-frame deletion of a 36-amino acid sequence encoded by exon 10. Analysis of chromosome 4 using short tandem repeat polymorphic markers revealed that the proband had inherited only maternal alleles in chromosome 4q spanning a 150-cM region; i.e., there was segmental maternal isodisomy 4q21-q35, probably due to mitotic recombination. Nonpaternity was excluded using polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal uniparental disomy 4q) was the basis for homozygosity of the MTP gene mutation in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10446076" 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> rs199422220 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422220;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/rs199422220?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=rs199422220" 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=rs199422220" 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=RCV000015306 OR RCV001222493" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015306, RCV001222493" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015306...</a>
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<p>In a patient with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>) in whom <a href="#19" class="mim-tip-reference" title="Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., Gregg, R. E. <strong>Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.</strong> Science 258: 999-1001, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1439810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1439810</a>] [<a href="https://doi.org/10.1126/science.1439810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1439810">Wetterau et al. (1992)</a> could detect no large subunit of MTP, <a href="#13" class="mim-tip-reference" title="Rehberg, E. F., Samson-Bouma, M.-E., Kienzle, B., Blinderman, L., Jamil, H., Wetterau, J. R., Aggerbeck, L. P., Gordon, D. A. <strong>A novel abetalipoproteinemia genotype: identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.</strong> J. Biol. Chem. 271: 29945-29952, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939939</a>] [<a href="https://doi.org/10.1074/jbc.271.47.29945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939939">Rehberg et al. (1996)</a> performed sequence analysis of cDNAs from additional intestinal biopsies and showed that the patient was a compound heterozygote for mutations in the MTP gene. One allele contained a perfect in-frame deletion of exon 10 (<a href="#0005">157147.0005</a>), explaining the lower molecular weight band demonstrated by electrophoresis. <a href="#13" class="mim-tip-reference" title="Rehberg, E. F., Samson-Bouma, M.-E., Kienzle, B., Blinderman, L., Jamil, H., Wetterau, J. R., Aggerbeck, L. P., Gordon, D. A. <strong>A novel abetalipoproteinemia genotype: identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.</strong> J. Biol. Chem. 271: 29945-29952, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939939</a>] [<a href="https://doi.org/10.1074/jbc.271.47.29945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939939">Rehberg et al. (1996)</a> found that cDNAs of the second allele contained 3 missense mutations. Transient expression of each mutant showed that only one, arg540 to his (R450H), was nonfunctional based upon its inability to reconstitute apoB secretion in a cell culture system. The other 2 amino acid changes were silent polymorphisms. High level coexpression in a baculovirus system of the wildtype 97-kD subunit or the R540H mutant with human protein disulfide isomerase (<a href="/entry/176790">176790</a>) showed that the wildtype was capable of forming an active MTP complex while the mutant was not. Analysis of lysates from these cells showed that the arg-to-his conversion interrupted the interaction between the 97-kD subunit and protein disulfide isomerase. Replacement of arg540 with a lysine residue maintained the ability of the large subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. This result indicated that a positively charged amino acid at position 540 in the large subunit is critical for the productive association with protein disulfide isomerase. <a href="#13" class="mim-tip-reference" title="Rehberg, E. F., Samson-Bouma, M.-E., Kienzle, B., Blinderman, L., Jamil, H., Wetterau, J. R., Aggerbeck, L. P., Gordon, D. A. <strong>A novel abetalipoproteinemia genotype: identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.</strong> J. Biol. Chem. 271: 29945-29952, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939939</a>] [<a href="https://doi.org/10.1074/jbc.271.47.29945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939939">Rehberg et al. (1996)</a> stated that of the 13 mutant MTP 97-kD subunit alleles described up to that time this was the first encoding a missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1439810+8939939" 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://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015307</a>
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<p>For discussion of the in-frame deletion of exon 10 in the MTTP gene that was identified in compound heterozygous state in a patient with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>) by <a href="#13" class="mim-tip-reference" title="Rehberg, E. F., Samson-Bouma, M.-E., Kienzle, B., Blinderman, L., Jamil, H., Wetterau, J. R., Aggerbeck, L. P., Gordon, D. A. <strong>A novel abetalipoproteinemia genotype: identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.</strong> J. Biol. Chem. 271: 29945-29952, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939939</a>] [<a href="https://doi.org/10.1074/jbc.271.47.29945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939939">Rehberg et al. (1996)</a>, see <a href="#0005">157147.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8939939" 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 ABETALIPOPROTEINEMIA</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">rs199422221 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422221;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=rs199422221" 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=rs199422221" 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=RCV000015308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015308</a>
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<p>In a 27-year-old Japanese male with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>) who had no history of steatorrhea or other medical problems but who was found to be extremely hypolipemic during a routine medical exam, <a href="#10" class="mim-tip-reference" title="Ohashi, K., Ishibashi, S., Osuga, J., Tozawa, R., Harada, K., Yahagi, N., Shionoiri, F., Iizuka, Y., Tamura, Y., Nagai, R., Illingworth, D. R., Gotoda, T., Yamada, N. <strong>Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.</strong> J. Lipid Res. 41: 1199-1204, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946006</a>]" pmid="10946006">Ohashi et al. (2000)</a> identified homozygosity for an asn780-to-tyr (N780Y) missense mutation in the MTP gene. His parents were consanguineous. The patient showed neither neurologic nor ophthalmologic abnormalities; however, acanthocytosis and mild fatty liver were detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946006" 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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MTTP, SER590ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199422222 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422222;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=rs199422222" 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=rs199422222" 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=RCV000015309" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015309" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015309</a>
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<p>In a 58-year-old man with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>), <a href="#1" class="mim-tip-reference" title="Al-Shali, K., Wang, J., Rosen, F., Hegele, R. A. <strong>Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia.</strong> Clin. Genet. 63: 135-138, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630961</a>] [<a href="https://doi.org/10.1046/j.0009-9163.2002.00175.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630961">Al-Shali et al. (2003)</a> identified homozygosity for a ser590-to-ile (S590I) mutation in the MTP gene. The patient had a lifelong history of fat malabsorption, but the diagnosis of abetalipoproteinemia was not made until age 52 years, based on absence of apolipoprotein B-containing lipoproteins, acanthocytosis, atypical retinitis pigmentosa, and markedly depressed serum beta-carotene concentration. His presentation was notable not only by survival to the sixth decade of life without specific treatment, but also by the absence of neurologic involvement and by normal serum vitamin E concentration. He subsequently developed adenocarcinoma of the ileum, which required ileal resection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630961" 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 RECLASSIFIED - MTTP POLYMORPHISM</strong>
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MTTP, ILE128THR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3816873;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3816873</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3816873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3816873;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/rs3816873?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=rs3816873" 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=rs3816873" 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=RCV000015310 OR RCV000117636 OR RCV000333725 OR RCV001522091 OR RCV002496371" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015310, RCV000117636, RCV000333725, RCV001522091, RCV002496371" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015310...</a>
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<p>This variant, formerly titled METABOLIC SYNDROME, PROTECTION AGAINST, has been reclassified as a polymorphism.</p><p><a href="#14" class="mim-tip-reference" title="Rubin, D., Helwig, U., Pfeuffer, M., Schreiber, S., Boeing, H., Fisher, E., Pfeiffer, A., Freitag-Wolf, S., Foelsch, U. R., Doering, F., Schrezenmeir, J. <strong>A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.</strong> J. Hum. Genet. 51: 567-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16721486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16721486</a>] [<a href="https://doi.org/10.1007/s10038-006-0400-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16721486">Rubin et al. (2006)</a> genotyped a cohort of 716 German men for the functional MTP exon polymorphism ile128-to-thr (I128T) and found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (<a href="/entry/125853">125853</a>). Consistent with these findings, in a nested case-control study of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls, <a href="#14" class="mim-tip-reference" title="Rubin, D., Helwig, U., Pfeuffer, M., Schreiber, S., Boeing, H., Fisher, E., Pfeiffer, A., Freitag-Wolf, S., Foelsch, U. R., Doering, F., Schrezenmeir, J. <strong>A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.</strong> J. Hum. Genet. 51: 567-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16721486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16721486</a>] [<a href="https://doi.org/10.1007/s10038-006-0400-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16721486">Rubin et al. (2006)</a> observed a lower incidence of type 2 diabetes in individuals with the thr128 genotype (p = 0.007). <a href="#14" class="mim-tip-reference" title="Rubin, D., Helwig, U., Pfeuffer, M., Schreiber, S., Boeing, H., Fisher, E., Pfeiffer, A., Freitag-Wolf, S., Foelsch, U. R., Doering, F., Schrezenmeir, J. <strong>A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.</strong> J. Hum. Genet. 51: 567-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16721486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16721486</a>] [<a href="https://doi.org/10.1007/s10038-006-0400-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16721486">Rubin et al. (2006)</a> suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome (see <a href="/entry/605552">605552</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16721486" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. March 29, 2023."None>Hamosh (2023)</a> noted that the I128T variant was present in 69,405 of 279,940 alleles and in 9,277 homozygotes, for an allele frequency of 0.2479 in the gnomAD database.</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> rs146064714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs146064714;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/rs146064714?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=rs146064714" 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=rs146064714" 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=RCV000015311 OR RCV000760413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015311, RCV000760413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015311...</a>
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<p>In 3 unrelated Ashkenazi Jewish families from Israel with abetalipoproteinemia (ABL; <a href="/entry/200100">200100</a>), <a href="#2" class="mim-tip-reference" title="Benayoun, L., Granot, E., Rizel, L., Allon-Shalev, S., Behar, D. M., Ben-Yosef, T. <strong>Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.</strong> Molec. Genet. Metab. 90: 453-457, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17275380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17275380</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17275380">Benayoun et al. (2007)</a> demonstrated that probands were homozygous for a G-to-T transversion at position 2593 in exon 18 of the MTP gene, resulting in a glycine-to-termination substitution at codon 865 (G865X). This mutation was also found in 3 of 786 Ashkenazi Jewish control chromosomes, thus indicating a carrier frequency of 1 in 131 (0.76; 95% confidence interval 0 to 1.8%) in this population. The carrier frequency suggested an abetalipoproteinemia incidence rate of approximately 1 in 69,000 in this population. G865X was not found among 480 chromosomes from non-Ashkenazi Jews. All chromosomes harboring G865X shared the same haplotype of 2 genetic markers which span 208 kb flanking the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17275380" 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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Clin. Genet. 63: 135-138, 2003.
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<a id="19" class="mim-anchor"></a>
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<a id="Wetterau1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., Gregg, R. E.
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<strong>Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.</strong>
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Science 258: 999-1001, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1439810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1439810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1439810" 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/10.1126/science.1439810" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Wetterau1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wetterau, J. R., Combs, K. A., Spinner, S. N., Joiner, B. J.
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<strong>Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex.</strong>
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J. Biol. Chem. 265: 9800-9807, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2351674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2351674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2351674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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<a id="21" class="mim-anchor"></a>
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<a id="Yang1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, X. P., Inazu, A., Yagi, K., Kajinami, K., Koizumi, J., Mabuchi, H.
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<strong>Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene.</strong>
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Arterioscler. Thromb. Vasc. Biol. 19: 1950-1955, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10446076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10446076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10446076" 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/10.1161/01.atv.19.8.1950" target="_blank">Full Text</a>]
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</ol>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Ada Hamosh - updated : 3/24/2023
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 6/22/2007<br>Victor A. McKusick - updated : 6/11/2007<br>Marla J. F. O'Neill - updated : 12/12/2006<br>Victor A. McKusick - updated : 4/22/2003<br>Victor A. McKusick - updated : 6/4/2002<br>Stylianos E. Antonarakis - updated : 9/14/1999<br>Victor A. McKusick - updated : 5/20/1999<br>Victor A. McKusick - updated : 7/7/1998
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/17/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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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carol : 03/30/2023
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/24/2023<br>carol : 03/23/2023<br>joanna : 03/06/2019<br>carol : 09/05/2018<br>carol : 09/08/2015<br>joanna : 10/27/2010<br>alopez : 6/22/2007<br>alopez : 6/15/2007<br>terry : 6/11/2007<br>wwang : 12/14/2006<br>terry : 12/12/2006<br>tkritzer : 4/29/2003<br>terry : 4/22/2003<br>alopez : 6/12/2002<br>terry : 6/4/2002<br>mgross : 9/14/1999<br>mgross : 6/4/1999<br>mgross : 5/28/1999<br>terry : 5/20/1999<br>carol : 11/12/1998<br>carol : 7/9/1998<br>terry : 7/7/1998<br>terry : 6/1/1998<br>mark : 9/1/1997<br>mark : 5/9/1996<br>terry : 5/7/1996<br>terry : 4/30/1996<br>joanna : 1/4/1996<br>mark : 12/15/1995<br>terry : 12/13/1995<br>carol : 1/19/1995<br>davew : 7/14/1994<br>warfield : 4/21/1994<br>carol : 9/17/1993
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</span>
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</div>
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<span class="mim-font">
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<strong>*</strong> 157147
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; MTTP
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</h3>
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<div>
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<br />
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MTP<br />
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MTP, LARGE SUBUNIT
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<div>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MTTP</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 190787008;
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<strong>ICD10CM:</strong> E78.6;
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<strong>
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<em>
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Cytogenetic location: 4q23
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:99,564,130-99,623,997 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<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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<td rowspan="1">
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<span class="mim-font">
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4q23
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<td>
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<span class="mim-font">
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Abetalipoproteinemia
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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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200100
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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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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3
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</td>
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</tbody>
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. It is a heterodimer composed of a 55-kD multifunctional protein, protein disulfide isomerase (P4HB; 176790), and a unique large subunit with an apparent molecular weight of 88 kD (Wetterau et al., 1990). MTP was isolated as a soluble protein from the lumen of a microsomal fraction of liver and intestine. (Rehberg et al. (1996) referred to the large subunit as the 97-kD subunit.) </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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sharp et al. (1993) isolated and sequenced cDNA encoding the large subunit of MTP. A comparison of the normal sequence with the genomic sequences from 2 abetalipoproteinemic subjects demonstrated a homozygous frameshift mutation in one and a homozygous nonsense mutation in the other. </p><p>Nakamuta et al. (1996) cloned and sequenced mouse MTP cDNA. The DNA-deduced amino acid sequence indicated that mouse MTP contains 894 amino acids; the mouse protein showed 93, 86, and 83% sequence identity to the hamster, human, and bovine sequences, respectively. Northern blot analysis indicated that mouse MTP mRNA is expressed at high levels in the small intestine and at substantially lower levels in the liver; it was not detectable in 6 other tissues examined. The authors noted that the C-terminal region of MTP was more highly conserved than the N-terminal region in human, bovine, hamster, and mouse. </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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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The MTP gene has 17 introns (Shoulders et al., 1994). </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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<h4>
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<span class="mim-font">
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<strong>Gene Family</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shoulders et al. (1994) pointed out that MTP has amino acid sequence homology with lipovitellin, a component of an ancient transport and storage lipoprotein found in egg-laying animals. Lipovitellin is derived by proteolytic cleavage of vitellogenin, which is synthesized in the liver under estrogen control, and serves as a source of lipids and amino acids during embryogenesis. Shoulders et al. (1994) showed the MTP is a member of the vitellogenin gene family. </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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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR analysis of rodent/human somatic cell hybrids followed by fluorescence in situ hybridization, Narcisi et al. (1995) mapped the MTP gene to 4q22-q24. By Southern blots of interspecific backcross panels, Nakamuta et al. (1996) mapped the mouse Mtp gene to distal chromosome 3. </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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<h4>
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<span class="mim-font">
|
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<strong>Biochemical Features</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>Wetterau et al. (1992) reported that the large subunit of MTP was not detectable in 4 unrelated subjects with abetalipoproteinemia (ABL; 200100), a rare autosomal recessive disease characterized by a defect in assembly or secretion of plasma lipoproteins that contain apolipoprotein B (APOB; 107730). </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Abetalipoproteinemia</em></strong></p><p>
|
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In a cohort of 8 patients with classic abetalipoproteinemia, Narcisi et al. (1995) identified a mutation of the MTP gene in both alleles of all individuals. Each mutant allele was predicted to encode a truncated form of MTP with a variable number of aberrant amino acids at its C-terminal end. Expression of genetically engineered forms of MTP in COS-1 cells indicated to the authors that the C-terminal portion of MTP is necessary for triglyceride-transfer activity. A deletion of 20 amino acids from the carboxyl terminus of the 894-amino acid protein and a missense mutation of cys878-to-ser both abolished activity. </p><p>Heath et al. (1997) described a highly informative CA repeat polymorphism within the MTP gene which can be used for diagnosis, including prenatal diagnosis, in lieu of a mutation search, which can be difficult. </p><p>Ohashi et al. (2000) stated that 14 separate mutations in the MTP gene and/or cDNA from patients with abetalipoproteinemia had been described. They identified MTP mutations in all 8 alleles of 2 Japanese and 2 American patients with ABL. These included a second incidence of a missense mutation (157147.0007; see 157147.0005 for the first missense mutation described). </p><p>Benayoun et al. (2007) investigated the genetic basis for abetalipoproteinemia in a cohort of Israeli families. In Ashkenazi Jewish patients, Benayoun et al. (2007) identified a conserved haplotype and a common MTP mutation, gly865 to ter (157147.0010), with a carrier frequency of 1:131 in this population. They also reported the first case of abetalipoproteinemia and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 kb, including MTP and 8 other genes. </p><p>Cuchel et al. (2007) reported that inhibition of the microsomal triglyceride transfer protein reduces plasma low density lipoprotein (LDL) cholesterol in homozygous familial hypercholesterolemia (143890). Treatment-related hepatic steatosis was predictable from studies in animals, variable among study subjects, and reversible with discontinuation of the inhibitor. Hegele (2007) suggested that clues to the long-term consequences of inhibition of the microsomal triglyceride transfer protein might be found among patients with abetalipoproteinemia (200100). Cirrhosis has been reported in patients with abetalipoproteinemia (Partin et al., 1974). Fat accumulation within enterocytes and steatorrhea are defining features of abetalipoproteinemia; ileal adenocarcinoma developed in one patient with abetalipoproteinemia who survived for a long period (Al-Shali et al., 2003). Cuchel and Rader (2007) agreed with the suggestions of Hegele (2007). </p><p><strong><em>MTTP Polymorphisms</em></strong></p><p>
|
|
In a cohort of 716 German men genotyped for the ile128-to-thr polymorphism of the MTP gene (I128T; 157147.0009), Rubin et al. (2006) found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (125853). In a case-control study of 190 patients with type 2 diabetes and 380 controls, Rubin et al. (2006) observed a significantly lower incidence of type 2 diabetes in individuals with the thr128 genotype; the authors suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome. </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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<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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</div>
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<span class="mim-text-font">
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<p>Although deficiency in MTP causes abetalipoproteinemia, the role of MTP in the assembly and secretion of very low density lipoprotein (VLDL) in the liver was not precisely understood. To this end, Raabe et al. (1999) knocked out the Mtp gene in the mouse. Achieving the objective was thwarted by a lethal embryonic phenotype. Raabe et al. (1999) found, however, that they could produce mice harboring a 'floxed' Mtp allele and then use Cre-mediated recombination to generate liver-specific Mtp knockout mice. Inactivation of the Mtp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and high density lipoprotein (HDL) cholesterol levels. Mtp gene inactivation lowered apoB-100 levels in the plasma by more than 95% but reduced plasma apoB-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wildtype mouse liver revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (endoplasmic reticulum (ER) and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. Raabe et al. (1999) concluded that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apoB-100 from the liver. </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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<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>10 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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ABETALIPOPROTEINEMIA</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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MTTP, 1-BP DEL, 215C
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<br />
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SNP: rs1560614154,
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ClinVar: RCV000015302, RCV003556023
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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 39-year-old female with abetalipoproteinemia (ABL; 200100), the offspring of a consanguineous mating, Sharp et al. (1993) isolated total RNA and reverse transcribed it into first-strand cDNA. The cDNA encoding the large subunit of MTP was amplified by PCR and sequenced directly. Three independent PCR products revealed a cytosine deletion at base 215. The frameshift mutation led to a premature stop codon 21 bases downstream and a predicted translation product of 78 amino acids. The 187-bp exon that encoded the mutation was amplified from the subject's genomic DNA and sequenced directly. A single sequence that contained the frameshift mutation was observed, indicating that both alleles contained the defect, i.e., that the patient was homozygous. </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>.0002 ABETALIPOPROTEINEMIA</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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MTTP, ARG215TER
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<br />
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SNP: rs199422219,
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ClinVar: RCV000015303, RCV001851870, RCV003398517
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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>Sharp et al. (1993) constructed a genomic library from the DNA of a 14-year-old abetalipoproteinemic (ABL; 200100) female previously shown to lack MTP (Wetterau et al., 1992) and isolated clones encoding the large subunit of MTP. Sequence analysis revealed a C-to-T mutation corresponding to base 1783 of the cDNA. The mutation changed an arg codon to a premature stop codon. A truncated translation product of 594 amino acids was predicted. The nonsense mutation also eliminated a TaqI restriction endonuclease site. The normal exon encoding base 1783 was digested into 2 fragments by TaqI. DNA from the abetalipoproteinemic subject was not digested at this site, indicating that both alleles contained the defect, i.e., the subject was homozygous. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 ABETALIPOPROTEINEMIA</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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MTTP, IVS, G-A, +5
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<br />
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SNP: rs1429774833,
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gnomAD: rs1429774833,
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ClinVar: RCV000015304, RCV003556024
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In sibs with abetalipoproteinemia (ABL; 200100) reported by Talmud et al. (1988), Shoulders et al. (1993) demonstrated homozygosity for a splice mutation in the MTP protein. RT-PCR of mRNA prepared from intestinal biopsies from one of the patients provided starting material. By sequencing genomic and cDNA clones from the patient, Shoulders et al. (1993) demonstrated that the patient's cDNA contained an abnormal 91-bp sequence at the site of an intron/exon splice junction between nucleotides 1867 and 1868 encoding amino acid codon 623. The DNA sequence 3-prime of nucleotide 1867 encoded 31 amino acids before an in-frame stop codon was encountered. No abnormality of the invariant GT and AG intron/exon consensus sequences was found. Sequencing of genomic clones from each parent demonstrated a G-to-A substitution at the +5 position of the 5-prime splice site in 1 allele. All of the patient's cDNA and genomic clones bore an A at this position. Thus, the patient had an exon skip, causing a frameshift and the generation of a premature UAG stop codon at nucleotides 1869-1871 of the cDNA. The G-to-A mutation at the +5 position of a splice donor site was associated with production of 2 mRNA species: one failed to splice the intron containing the mutation, and the other skipped the exon immediately upstream. </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>
|
|
<span class="mim-font">
|
|
<strong>.0004 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
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MTTP, IVS9AS, G-A, -1
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<br />
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SNP: rs1560621444,
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ClinVar: RCV000015305
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 29-year-old Japanese male with abetalipoproteinemia (ABL; 200100), Yang et al. (1999) identified a homozygous G-to-A transition at the -1 position of the intron 9 splice acceptor site of the MTP gene. This mutation alters the splicing of the mRNA, resulting in an in-frame deletion of a 36-amino acid sequence encoded by exon 10. Analysis of chromosome 4 using short tandem repeat polymorphic markers revealed that the proband had inherited only maternal alleles in chromosome 4q spanning a 150-cM region; i.e., there was segmental maternal isodisomy 4q21-q35, probably due to mitotic recombination. Nonpaternity was excluded using polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal uniparental disomy 4q) was the basis for homozygosity of the MTP gene mutation in this patient. </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>.0005 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, ARG540HIS
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|
<br />
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|
|
SNP: rs199422220,
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|
|
|
gnomAD: rs199422220,
|
|
|
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|
|
ClinVar: RCV000015306, RCV001222493
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with abetalipoproteinemia (ABL; 200100) in whom Wetterau et al. (1992) could detect no large subunit of MTP, Rehberg et al. (1996) performed sequence analysis of cDNAs from additional intestinal biopsies and showed that the patient was a compound heterozygote for mutations in the MTP gene. One allele contained a perfect in-frame deletion of exon 10 (157147.0005), explaining the lower molecular weight band demonstrated by electrophoresis. Rehberg et al. (1996) found that cDNAs of the second allele contained 3 missense mutations. Transient expression of each mutant showed that only one, arg540 to his (R450H), was nonfunctional based upon its inability to reconstitute apoB secretion in a cell culture system. The other 2 amino acid changes were silent polymorphisms. High level coexpression in a baculovirus system of the wildtype 97-kD subunit or the R540H mutant with human protein disulfide isomerase (176790) showed that the wildtype was capable of forming an active MTP complex while the mutant was not. Analysis of lysates from these cells showed that the arg-to-his conversion interrupted the interaction between the 97-kD subunit and protein disulfide isomerase. Replacement of arg540 with a lysine residue maintained the ability of the large subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. This result indicated that a positively charged amino acid at position 540 in the large subunit is critical for the productive association with protein disulfide isomerase. Rehberg et al. (1996) stated that of the 13 mutant MTP 97-kD subunit alleles described up to that time this was the first encoding a missense mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, EX10DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the in-frame deletion of exon 10 in the MTTP gene that was identified in compound heterozygous state in a patient with abetalipoproteinemia (ABL; 200100) by Rehberg et al. (1996), see 157147.0005. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, ASN780TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422221,
|
|
|
|
|
|
|
|
ClinVar: RCV000015308
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 27-year-old Japanese male with abetalipoproteinemia (ABL; 200100) who had no history of steatorrhea or other medical problems but who was found to be extremely hypolipemic during a routine medical exam, Ohashi et al. (2000) identified homozygosity for an asn780-to-tyr (N780Y) missense mutation in the MTP gene. His parents were consanguineous. The patient showed neither neurologic nor ophthalmologic abnormalities; however, acanthocytosis and mild fatty liver were detected. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, SER590ILE
|
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|
|
|
<br />
|
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|
|
SNP: rs199422222,
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|
|
|
|
|
|
|
ClinVar: RCV000015309
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 58-year-old man with abetalipoproteinemia (ABL; 200100), Al-Shali et al. (2003) identified homozygosity for a ser590-to-ile (S590I) mutation in the MTP gene. The patient had a lifelong history of fat malabsorption, but the diagnosis of abetalipoproteinemia was not made until age 52 years, based on absence of apolipoprotein B-containing lipoproteins, acanthocytosis, atypical retinitis pigmentosa, and markedly depressed serum beta-carotene concentration. His presentation was notable not only by survival to the sixth decade of life without specific treatment, but also by the absence of neurologic involvement and by normal serum vitamin E concentration. He subsequently developed adenocarcinoma of the ileum, which required ileal resection. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 RECLASSIFIED - MTTP POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, ILE128THR ({dbSNP rs3816873})
|
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|
|
<br />
|
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|
|
SNP: rs3816873,
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|
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gnomAD: rs3816873,
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|
|
ClinVar: RCV000015310, RCV000117636, RCV000333725, RCV001522091, RCV002496371
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled METABOLIC SYNDROME, PROTECTION AGAINST, has been reclassified as a polymorphism.</p><p>Rubin et al. (2006) genotyped a cohort of 716 German men for the functional MTP exon polymorphism ile128-to-thr (I128T) and found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (125853). Consistent with these findings, in a nested case-control study of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls, Rubin et al. (2006) observed a lower incidence of type 2 diabetes in individuals with the thr128 genotype (p = 0.007). Rubin et al. (2006) suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome (see 605552). </p><p>Hamosh (2023) noted that the I128T variant was present in 69,405 of 279,940 alleles and in 9,277 homozygotes, for an allele frequency of 0.2479 in the gnomAD database.</p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ABETALIPOPROTEINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTTP, GLY865TER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs146064714,
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|
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|
|
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gnomAD: rs146064714,
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|
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|
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ClinVar: RCV000015311, RCV000760413
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|
|
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated Ashkenazi Jewish families from Israel with abetalipoproteinemia (ABL; 200100), Benayoun et al. (2007) demonstrated that probands were homozygous for a G-to-T transversion at position 2593 in exon 18 of the MTP gene, resulting in a glycine-to-termination substitution at codon 865 (G865X). This mutation was also found in 3 of 786 Ashkenazi Jewish control chromosomes, thus indicating a carrier frequency of 1 in 131 (0.76; 95% confidence interval 0 to 1.8%) in this population. The carrier frequency suggested an abetalipoproteinemia incidence rate of approximately 1 in 69,000 in this population. G865X was not found among 480 chromosomes from non-Ashkenazi Jews. All chromosomes harboring G865X shared the same haplotype of 2 genetic markers which span 208 kb flanking the mutation. </p>
|
|
</span>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Al-Shali, K., Wang, J., Rosen, F., Hegele, R. A.
|
|
<strong>Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia.</strong>
|
|
Clin. Genet. 63: 135-138, 2003.
|
|
|
|
|
|
[PubMed: 12630961]
|
|
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|
|
|
[Full Text: https://doi.org/10.1046/j.0009-9163.2002.00175.x]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
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