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Entry
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- *276000 - PROTEASE, SERINE, 1; PRSS1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*276000</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</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="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/276000">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000204983;t=ENST00000311737" 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=5644" 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=276000" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000204983;t=ENST00000311737" 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_002769,NR_172947,NR_172948,NR_172949,NR_172950,NR_172951" 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_002769" 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=276000" 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=02039&isoform_id=02039_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/PRSS1" 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/136408,521216,1552515,1616766,4261620,4506145,10304613,11120616,11120624,11120626,11120628,29649713,29649727,29649737,29649748,29649763,29649776,29649786,31095599,31095601,32250962,32250964,32408795,51094518,71738264,114318997,116001092,118764023,119572310,161728076,161728218,161728222,161728268,161728274,189053326,194373583" 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/P07477" 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=5644" 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=ENSG00000204983;t=ENST00000311737" 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=PRSS1" 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=PRSS1" 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+5644" 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/PRSS1" 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:5644" 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/5644" 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=chr7&hgg_gene=ENST00000311737.12&hgg_start=142749472&hgg_end=142753072&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9475" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9475" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/prss1" 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=276000[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=276000[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/ENSG00000204983" 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=PRSS1" 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=PRSS1" 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=PRSS1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.uni-leipzig.de/pancreasmutation/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PRSS1&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/PA33828" 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:9475" 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/FBgn0015316.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/search?q=MGI:102756 MGI:102757 MGI:102758 MGI:3641889 MGI:3646222 MGI:3687012 MGI:98839" 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/PRSS1#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/batch/summary?idType=MGI&ids=MGI:102756 MGI:102757 MGI:102758 MGI:3641889 MGI:3646222 MGI:3687012 MGI:98839" 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/5644/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=5644" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-010131-7" 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">
|
|
<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:5644" 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=PRSS1&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> 235956004, 68072000<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">
|
|
<span class="text-danger"><strong>*</strong></span>
|
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276000
|
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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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PROTEASE, SERINE, 1; PRSS1
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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">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
TRYPSINOGEN 1; TRY1<br />
|
|
TRYPSINOGEN, CATIONIC
|
|
</span>
|
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</h4>
|
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</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TRYPSIN 1, INCLUDED
|
|
</span>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PRSS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PRSS1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/754?start=-3&limit=10&highlight=754">7q34</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:142749472-142753072&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'})">7:142,749,472-142,753,072</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/754?start=-3&limit=10&highlight=754">
|
|
7q34
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Pancreatitis, hereditary
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/167800"> 167800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<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>
|
|
</td>
|
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|
|
|
|
</tr>
|
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|
|
</tbody>
|
|
</table>
|
|
</div>
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</div>
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<div>
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<p>Human pancreatic juice contains 3 isoforms of trypsinogen. On the basis of their relative electrophoretic mobility, these are commonly referred to as cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2; <a href="/entry/601564">601564</a>), and mesotrypsinogen (PRSS3; <a href="/entry/613578">613578</a>). Normally, cationic trypsinogen represents approximately two-thirds of total trypsinogen, while anionic trypsinogen makes up approximately one-third. Mesotrypsinogen is a minor species, accounting for less than 5% of trypsinogens or 0.5% of pancreatic juice proteins (<a href="#26" class="mim-tip-reference" title="Scheele, G., Bartelt, D., Bieger, W. <strong>Characterization of human exocrine pancreatic proteins by two-dimensional isoelectric focusing/sodium dodecyl sulfate gel electrophoresis.</strong> Gastroenterology 80: 461-473, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6969677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6969677</a>]" pmid="6969677">Scheele et al., 1981</a>; <a href="#20" class="mim-tip-reference" title="Rinderknecht, H., Renner, I. G., Abramson, S. B., Carmack, C. <strong>Mesotrypsin: a new inhibitor-resistant protease from a zymogen in human pancreatic tissue and fluid.</strong> Gastroenterology 86: 681-692, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6698368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6698368</a>]" pmid="6698368">Rinderknecht et al. (1984)</a>; summary by <a href="#31" class="mim-tip-reference" title="Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M. <strong>Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).</strong> Hum. Mutat. 23: 22-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14695529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14695529</a>] [<a href="https://doi.org/10.1002/humu.10285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14695529">Teich et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14695529+6698368+6969677" 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>Trypsin (<a href="https://enzyme.expasy.org/EC/3.4.21.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.4.21.4</a>) is a member of the pancreatic family of serine proteases.</p>
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<p><a href="#18" class="mim-tip-reference" title="MacDonald, R. J., Stary, S. J., Swift, G. H. <strong>Two similar but nonallelic rat pancreatic trypsinogens: nucleotide sequences of the cloned cDNAs.</strong> J. Biol. Chem. 257: 9724-9732, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6896710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6896710</a>]" pmid="6896710">MacDonald et al. (1982)</a> reported nucleotide sequences of cDNAs representing 2 pancreatic rat trypsinogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6896710" 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="Emi, M., Nakamura, Y., Ogawa, M., Yamamoto, T., Nishide, T., Mori, T., Matsubara, K. <strong>Cloning, characterization and nucleotide sequences of two cDNAs encoding human pancreatic trypsinogens.</strong> Gene 41: 305-310, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3011602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3011602</a>] [<a href="https://doi.org/10.1016/0378-1119(86)90111-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3011602">Emi et al. (1986)</a> isolated cDNA clones for 2 major human trypsinogen isozymes from a pancreatic cDNA library. The deduced amino acid sequences had 89% homology and the same number of amino acids (247), including a 15-amino acid signal peptide and an 8-amino acid activation peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3011602" 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="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> found that 2 of 3 pancreatically expressed trypsinogen cDNAs correspond to trypsinogen genes embedded in the beta T-cell receptor (TCRB; see <a href="/entry/186930">186930</a>) cluster of genes mapping to 7q35. T4 was denoted trypsinogen-1 and T8 was denoted trypsinogen-2 (<a href="/entry/601564">601564</a>). The third pancreatic cDNA, identified independently as trypsinogen-3 (<a href="#29" class="mim-tip-reference" title="Tani, T., Kawashima, I., Mita, K., Takiguchi, Y. <strong>Nucleotide sequence of the human pancreatic trypsinogen III cDNA.</strong> Nucleic Acids Res. 18: 1631 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2326201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2326201</a>] [<a href="https://doi.org/10.1093/nar/18.6.1631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2326201">Tani et al., 1990</a>) and -4 (<a href="#35" class="mim-tip-reference" title="Wiegand, U., Corbach, S., Minn, A., Kang, J., Muller-Hill, B. <strong>Cloning of the cDNA encoding human brain trypsinogen and characterization of its product.</strong> Gene 136: 167-175, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8294000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8294000</a>] [<a href="https://doi.org/10.1016/0378-1119(93)90460-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8294000">Wiegand et al., 1993</a>), is distinct from the third apparently functional trypsinogen gene (T6) in the TCRB locus but related to the other pancreatic trypsinogens. <a href="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> noted that the intercalation of the trypsinogen genes in the TCRB locus is conserved in mouse and chicken, suggesting shared functional or regulatory constraints, as has been postulated for genes in the major histocompatibility complex (such as class I, II, and III genes) that share similar long-term organizational relationships. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8650574+8294000+2326201" 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 alignment of pancreatic trypsinogen cDNAs with the germline sequences, <a href="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> showed that the trypsinogen genes contain 5 exons that span approximately 3.6 kb. Further analyses revealed 2 trypsinogen pseudogenes and 1 relic trypsinogen gene at the 5-prime end of the sequence, all in inverted transcriptional orientation. They denoted 8 trypsinogen genes T1 through T8 from 5-prime to 3-prime. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a rat cDNA probe, Honey et al. (<a href="#14" class="mim-tip-reference" title="Honey, N. K., Sakaguchi, A. Y., Quinto, C., MacDonald, R. J., Rutter, W. J., Bell, G. I., Naylor, S. L. <strong>Chromosomal assignments of the human genes for the serine proteases trypsin, chymotrypsin B, and elastase.</strong> Somat. Cell Molec. Genet. 10: 369-376, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6589790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6589790</a>] [<a href="https://doi.org/10.1007/BF01535632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6589790">1984</a>, <a href="#15" class="mim-tip-reference" title="Honey, N. K., Sakaguchi, A. Y., Quinto, C., MacDonald, R. J., Rutter, W. J., Naylor, S. L. <strong>Assignment of the human genes for elastase to chromosome 12, and for trypsin and carboxypeptidase A to chromosome 7. (Abstract)</strong> Cytogenet. Cell Genet. 37: 492 only, 1984."None>1984</a>) found that a 3.8-kb DNA fragment containing human trypsin-1 gene sequences cosegregated with chromosome 7, and assigned the gene further to 7q22-7qter by study of hybrids with a deletion of this segment. The trypsin gene is on mouse chromosome 6 (<a href="#13" class="mim-tip-reference" title="Honey, N. K., Sakaguchi, A. Y., Lalley, P. A., Quinto, C., MacDonald, R. J., Rutter, W. J., Bell, G. I., Naylor, S. L. <strong>Chromosomal assignments of the genes for trypsin, chymotrypsin B, and elastase in mouse.</strong> Somat. Cell Molec. Genet. 10: 377-383, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6589791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6589791</a>] [<a href="https://doi.org/10.1007/BF01535633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6589791">Honey et al., 1984</a>). Carboxypeptidase A (<a href="/entry/114850">114850</a>) and trypsin are a syntenic pair conserved in mouse and man. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6589790+6589791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Southern blot analysis of human genomic DNA with a cloned cDNA as probe, <a href="#8" class="mim-tip-reference" title="Emi, M., Nakamura, Y., Ogawa, M., Yamamoto, T., Nishide, T., Mori, T., Matsubara, K. <strong>Cloning, characterization and nucleotide sequences of two cDNAs encoding human pancreatic trypsinogens.</strong> Gene 41: 305-310, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3011602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3011602</a>] [<a href="https://doi.org/10.1016/0378-1119(86)90111-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3011602">Emi et al. (1986)</a> showed that the human trypsinogen genes constitute a family of more than 10, some of which may be pseudogenes or may be expressed in other stages of development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3011602" 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="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> mapped the gene corresponding to the third pancreatic trypsinogen cDNA by fluorescence in situ hybridization. They used a cosmid clone containing 3 trypsinogen genes. Strong hybridization to chromosome 7 and weaker hybridization to chromosome 9 were observed. They isolated and partially sequenced 4 cosmid clones from the chromosome 9 region. They found that the region represents a duplication and translocation of a DNA segment from the 3-prime end of the TCRB locus that includes at least 7 V(beta) elements and a functional trypsinogen gene denoted T9 (PRSS3; <a href="/entry/613578">613578</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650574" 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="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> found that there are 8 trypsinogen genes embedded in the beta T-cell receptor locus or cluster of genes (TCRB; see <a href="/entry/186930">186930</a>) mapping to 7q35. In the 685-kb DNA segment that they sequenced they found 5 tandemly arrayed 10-kb locus-specific repeats (homology units) at the 3-prime end of the locus. These repeats exhibited 90 to 91% overall nucleotide similarity, and embedded within each is a trypsinogen gene. Since hereditary pancreatitis (<a href="/entry/167800">167800</a>) had been mapped rather precisely to 7q35 and since a defect in the trypsinogen gene has been identified in hereditary pancreatitis, the assignment of the trypsinogen gene can be refined from 7q32-qter to 7q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8650574" 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="#34" class="mim-tip-reference" title="Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D. <strong>Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.</strong> Nature Genet. 14: 141-145, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841182</a>] [<a href="https://doi.org/10.1038/ng1096-141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841182">Whitcomb et al. (1996)</a> stated that the high degree of DNA sequence homology (more than 91%) present among this cluster of 5 trypsinogen genes identified by <a href="#22" class="mim-tip-reference" title="Rowen, L., Koop, B. F., Hood, L. <strong>The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.</strong> Science 272: 1755-1762, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8650574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8650574</a>] [<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8650574">Rowen et al. (1996)</a> demanded that highly specific sequence analysis strategies be developed for mutation screening in families with hereditary pancreatitis (<a href="/entry/167800">167800</a>). This was necessary to ensure that each sequencing run contained only the 2 alleles corresponding to a single gene, thereby permitting detection of heterozygotes in this autosomal dominant disorder, and not a dozen or more alleles from multiple related trypsinogen-like genes, which would make detection of heterozygotes nearly impossible. In a family with hereditary pancreatitis, <a href="#34" class="mim-tip-reference" title="Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D. <strong>Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.</strong> Nature Genet. 14: 141-145, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841182</a>] [<a href="https://doi.org/10.1038/ng1096-141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841182">Whitcomb et al. (1996)</a> found that affected individuals had a single G-to-A transition mutation in the third exon of cationic trypsinogen (<a href="#0001">276000.0001</a>). This mutation was predicted to result in an arg105-to-his substitution in the trypsin gene (residue number 122 in the more common trypsinogen number system; the residue has also been listed as 117; <a href="#0001">276000.0001</a>). Subsequently, the same mutation was found in a total of 5 different hereditary pancreatitis kindreds (4 from the U.S. and 1 from Italy) containing a total of 20 affected individuals and 6 obligate carriers. The mutation was found in none of the obligate unaffected members (individuals who married into the family). Subsequent haplotyping revealed that all 4 of the American families displayed the same high risk haplotype over a 4-cM region encompassing 7 STR markers, confirming the likelihood that these kindreds shared a common ancestor, although no link could be found through 8 generations. A fifth family from Italy displayed a unique haplotype indicating that the same mutation had occurred on at least 2 occasions. The G-to-A mutation at codon 122 created a novel enzyme recognition site for AflIII which provided a facile means to screen for the mutation. As with the obligate unaffected members of the pancreatitis kindreds, none of 140 controls possessed the G-to-A mutation as assayed by the lack of AflIII digestion of the amplified exonic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8841182+8650574" 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="Ferec, C., Raguenes, O., Salomon, R., Roche, C., Bernard, J. P., Guillot, M., Quere, I., Faure, C., Mercier, B., Audrezet, M. P., Guillausseau, P. J., Dupont, C., Munnich, A., Bignon, J. D., Le Bodic, L. <strong>Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.</strong> J. Med. Genet. 36: 228-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204851</a>]" pmid="10204851">Ferec et al. (1999)</a> studied 14 families with hereditary pancreatitis and found mutations in the PRSS1 gene in 8 families. In 4 of these families, the mutation (R122H; <a href="#0001">276000.0001</a>) had been described by <a href="#34" class="mim-tip-reference" title="Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D. <strong>Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.</strong> Nature Genet. 14: 141-145, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841182</a>] [<a href="https://doi.org/10.1038/ng1096-141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841182">Whitcomb et al. (1996)</a>. Three mutations were described in 4 other families (<a href="#0002">276000.0002</a>, <a href="#0003">276000.0003</a>, <a href="#0005">276000.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10204851+8841182" 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="#23" class="mim-tip-reference" title="Sahin-Toth, M., Graf, L., Toth, M. <strong>Trypsinogen stabilization by mutation arg117-to-his: a unifying pathomechanism for hereditary pancreatitis?</strong> Biochem. Biophys. Res. Commun. 264: 505-508, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10529393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10529393</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10529393">Sahin-Toth et al. (1999)</a> studied the roles of the 2 most frequent PRSS1 mutations in hereditary pancreatitis, R122H and N29I (<a href="#0002">276000.0002</a>). They stated that the R122H mutation is believed to cause pancreatitis by eliminating an essential autolytic cleavage site in trypsin, thereby rendering the protease resistant to inactivation through autolysis. <a href="#23" class="mim-tip-reference" title="Sahin-Toth, M., Graf, L., Toth, M. <strong>Trypsinogen stabilization by mutation arg117-to-his: a unifying pathomechanism for hereditary pancreatitis?</strong> Biochem. Biophys. Res. Commun. 264: 505-508, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10529393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10529393</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10529393">Sahin-Toth et al. (1999)</a> demonstrated that the R122H mutation also significantly inhibited autocatalytic trypsinogen breakdown under Ca(2+)-free conditions and stabilized the zymogen form of rat trypsin. Taken together with findings demonstrating that the N29I mutation stabilized rat trypsinogen against autoactivation and consequent autocatalytic degradation, the observations suggested a unifying molecular pathomechanism for hereditary pancreatitis in which zymogen stabilization plays a central role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10529393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Sahin-Toth, M., Toth, M. <strong>Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen.</strong> Biochem. Biophys. Res. Commun. 278: 286-289, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11097832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11097832</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11097832">Sahin-Toth and Toth (2000)</a> demonstrated that the R122H and N29I mutations significantly enhance autoactivation of human cationic trypsinogen in vitro, in a manner that correlates with the severity of clinical symptoms in hereditary pancreatitis. In addition, the R122H mutation inhibited autocatalytic inactivation of trypsin, while the N29I mutation had no such effect. Thus, increased trypsinogen activation in the pancreas is presumably the common initiating step in both forms of hereditary pancreatitis, whereas trypsin stabilization may also contribute to hereditary pancreatitis associated with the R122H mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11097832" 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="Chen, J.-M., Montier, T., Ferec, C. <strong>Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations.</strong> Hum. Genet. 109: 245-252, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702203</a>] [<a href="https://doi.org/10.1007/s004390100580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702203">Chen et al. (2001)</a> reviewed aspects of the molecular evolution and normal physiology of trypsinogen revealed by studies of PRSS1 in pancreatitis. First, the activation peptide of trypsinogen is under strong selection pressure to minimize autoactivation in higher vertebrates. Second, the R122 primary autolysis site (<a href="#0001">276000.0001</a>) has further evolved in mammalian trypsinogens. Third, evolutionary divergence from threonine to asparagine at residue 29 in human cationic trypsinogen provides additional advantage. Accordingly, <a href="#6" class="mim-tip-reference" title="Chen, J.-M., Montier, T., Ferec, C. <strong>Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations.</strong> Hum. Genet. 109: 245-252, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702203</a>] [<a href="https://doi.org/10.1007/s004390100580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702203">Chen et al. (2001)</a> tentatively assigned, in human cationic trypsinogen, the strongly selected activation peptide as the first line and the R122 autolysis site as the second line of the built-in defensive mechanisms against premature trypsin activation within the pancreas, and the positively selected asparagine at residue 29 as an 'amplifier' to the R122 'fail-safe' mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11702203" 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>Gene conversion--the substitution of genetic material from one gene to another--in most cases takes place between a normal gene and its pseudogene. <a href="#32" class="mim-tip-reference" title="Teich, N., Nemoda, Z., Kohler, H., Heinritz, W., Mossner, J., Keim, V., Sahin-Toth, M. <strong>Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl.</strong> Hum. Mutat. 25: 343-347, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15776435[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/10.1002/humu.20148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776435">Teich et al. (2005)</a> reported the occurrence of disease-associated gene conversion between 2 functional genes. They analyzed PRSS1 in 1,106 patients with chronic pancreatitis and in 1 patient identified a novel conversion event affecting exon 2 and the subsequent intron. The conversion replaced at least 289 nucleotides with the paralogous sequence from the PRSS2 gene and resulted in asn29-to-ile (N29I; <a href="#0002">276000.0002</a>) and asn54-to-ser (N54S) substitutions (<a href="#0007">276000.0007</a>). Analysis of the recombinant N29I/N54S double-mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N29I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776435" 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="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> interpreted the 365_366GC-AT R122H variant (<a href="#0008">276000.0008</a>) as an example of a gene conversion event. In most such cases, the donor gene is a duplicated pseudogene which has accumulated mutations over time. However, there is evidence that gene conversion can occur between 2 functional paralogous trypsinogen genes and cause chronic pancreatitis. Trypsinogen genes are tandemly repeated within the T-cell receptor beta locus (TCRB; see <a href="/entry/186930">186930</a>) on 7q35. This is a hotspot for gene conversion events to generate a broad variety of TCR-beta genes. Therefore, conversion mutation within the interpolated trypsinogen gene family are very likely to occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791840" 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="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> reviewed current information on trypsinogen mutations and their role in pancreatic diseases. They pointed out that, although the clinical presentation is highly variable, most affected mutation carriers have relatively mild disease. <a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> noted that, in addition to R122 mutations, pancreatitis-producing mutations had also been identified in the neighboring residues ala121 and val123. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791840" 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="#17" class="mim-tip-reference" title="Le Marechal, C., Masson, E., Chen, J.-M., Morel, F., Ruszniewski, P., Levy, P., Ferec, C. <strong>Hereditary pancreatitis caused by triplication of the trypsinogen locus.</strong> Nature Genet. 38: 1372-1374, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17072318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17072318</a>] [<a href="https://doi.org/10.1038/ng1904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17072318">Le Marechal et al. (2006)</a> reviewed observations suggesting that trypsinogen may be sensitive to a gene dosage effect. They noted that the R122H mutation (<a href="#0001">276000.0001</a>) and other pancreatitis-causing PRSS1 missense mutations show by in vitro functional analysis an increase in trypsin activity (see review by <a href="#25" class="mim-tip-reference" title="Sahin-Toth, M. <strong>Biochemical models of hereditary pancreatitis.</strong> Endocr. Metab. Clin. North Am. 35: 303-312, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632094</a>] [<a href="https://doi.org/10.1016/j.ecl.2006.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632094">Sahin-Toth, 2006</a>). On the other hand, an N34S variation (<a href="/entry/167790#0001">167790.0001</a>) in the SPINK1 gene and rare splicing and frameshifting mutations in that gene have been detected in individuals with chronic pancreatitis. SPINK1 encodes trypsin's physiologic inhibitor, the physiologic function of which appears to be the prevention of the trypsin-driven digestive enzyme activation cascade. Loss-of-function mutations in PRSS1 (<a href="#3" class="mim-tip-reference" title="Chen, J. M., Le Marechal, C., Lucas, D., Raguenes, O., Ferec, C. <strong>'Loss of function' mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis.</strong> Molec. Genet. Metab. 79: 67-70, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12765848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12765848</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00050-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12765848">Chen et al., 2003</a>) and a degradation-sensitive variant (G191R; <a href="/entry/601564#0001">601564.0001</a>) in the PRSS2 gene seem to confer protection against the disease. <a href="#17" class="mim-tip-reference" title="Le Marechal, C., Masson, E., Chen, J.-M., Morel, F., Ruszniewski, P., Levy, P., Ferec, C. <strong>Hereditary pancreatitis caused by triplication of the trypsinogen locus.</strong> Nature Genet. 38: 1372-1374, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17072318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17072318</a>] [<a href="https://doi.org/10.1038/ng1904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17072318">Le Marechal et al. (2006)</a> surmised that an increased copy number of the PRSS1 gene at 7q34 might account for some of the families with hereditary pancreatitis without a known causative mutation. They studied a well-characterized cohort of 34 French families with hereditary pancreatitis (defined as 3 or more affected family members involving at least 2 generations) who did not carry any causative point mutations in the PRSS1, PRSS2, SPINK1, and CFTR genes. Analysis of 1 affected individual per family suggested that the PRSS1 locus was triplicated, and this was confirmed in 5 of the analyzed families. Use of walking quantitative fluorescent multiplex PCR showed that the triplication extended approximately 605 kb and included all members of the trypsinogen gene family on chromosome 7. The size of the triplicated segment seemed to be the same in all carriers. Affected individuals in these families shared an identical haplotype that extended approximately 1,100 kb telomeric to the PRSS1 locus, suggesting that the triplication represents an identical-by-descent mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17072318+12765848+16632094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In all 6 affected members of a French family with chronic pancreatitis, <a href="#19" class="mim-tip-reference" title="Masson, E., Le Marechal, C., Delcenserie, R., Chen, J.-M., Ferec, C. <strong>Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation.</strong> Hum. Genet. 123: 521-529, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18461367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18461367</a>] [<a href="https://doi.org/10.1007/s00439-008-0508-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18461367">Masson et al. (2008)</a> identified the presence of a heterozygous PRSS1/PRSS2 hybrid gene. Quantitative fluorescent multiplex PCR and RT-PCR revealed duplication of exons 3 to 5 of PRSS1, and further analysis indicated that a nonallelic homologous recombination event resulted in the generation of a hybrid gene containing exons 1 and 2 from PRSS2 and exons 3 to 5 from PRSS1. This hybrid gene was predicted to encode a zymogen identical to a gene conversion-derived mutant cationic trypsinogen containing the N29I (<a href="#0002">276000.0002</a>) and N54S (<a href="#0007">276000.0007</a>) mutations. <a href="#19" class="mim-tip-reference" title="Masson, E., Le Marechal, C., Delcenserie, R., Chen, J.-M., Ferec, C. <strong>Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation.</strong> Hum. Genet. 123: 521-529, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18461367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18461367</a>] [<a href="https://doi.org/10.1007/s00439-008-0508-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18461367">Masson et al. (2008)</a> concluded that this hybrid gene caused the disease through an inherent double gain-of-function effect, acting simultaneously through an increased copy number effect and the N29I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18461367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> presented evidence that the A121T variant (<a href="#0011">276000.0011</a>) is functionally innocuous and not a cause of pancreatitis. The authors noted that only the index patient in the report of <a href="#9" class="mim-tip-reference" title="Felderbauer, P., Schnekenburger, J., Lebert, R., Bulut, K., Parry, M., Meister, T., Schick, V., Schmitz, F., Domschke, W., Schmidt, W. E. <strong>A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site.</strong> J. Med. Genet. 45: 507-512, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511571</a>] [<a href="https://doi.org/10.1136/jmg.2007.056481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511571">Felderbauer et al. (2008)</a> carried the A121T variant and suffered from chronic pancreatitis. The patient's brother and first cousin, who both carried the variant, had cholelithiasis, and his niece and her mother were asymptomatic carriers. Functional expression studies by <a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> indicated that autoactivation of trypsinogens by the A121T variant was similar to wildtype with equal enzyme kinetics. <a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> suggested that the variant may have been assigned clinical relevance based on a perceived analogy with the neighboring disease-causing R122H change (<a href="#0001">276000.0001</a> and <a href="#0008">276000.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18511571+20452997" 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="#12" class="mim-tip-reference" title="Gui, F., Zhang, Y., Wan, J., Zhan, X., Yao, Y., Li, Y., Haddock, A. N., Shi, J., Guo, J., Chen, J., Zhu, X., Edenfield, B. H., Zhuang, L., Hu, C., Wang, Y., Mukhopadhyay, D., Radisky, E. S., Zhang, L., Lugea, A., Pandol, S. J., Bi, Y., Ji, B. <strong>Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1-R122H.</strong> J. Clin. Invest. 130: 189-202, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31550238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31550238</a>] [<a href="https://doi.org/10.1172/JCI130172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31550238">Gui et al. (2020)</a> found that transgenic expression of full-length human PRSS1 with the R122H mutation in mice caused severe acute pancreatitis (AP) upon stimulation with cerulein. Cerulein induced mild AP in wildtype mice, with the mice recovering fully in a few days. In R122H transgenic mice, cerulein-induced AP failed to resolve and led to progressive pancreatic damage and activation of cellular stress signaling, resulting in chronic pancreatitis (CP) that resembled human hereditary pancreatitis caused by PRSS1 mutations. Human PRSS1 with the R122H mutation sensitized transgenic mice to development of cerulein-induced AP more severely than wildtype human PRSS1, because R122H was a gain-of-function mutation that increased trypsin activity. Treatment of R122H transgenic mice with trypsin inhibitors protected the pancreas from CP, and the anticoagulant dabigatran nearly abolished progression of CP. Anticoagulation and trypsin inhibition synergistically improved pancreatitis, as targeting both trypsin and coagulation pathways was required for effective pancreatitis therapy in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31550238" 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> rs111033565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033565;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/rs111033565?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=rs111033565" 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=rs111033565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The arg122-to-his mutation (R122H; previously designated ARG117HIS, or R117H, by the chymotrypsin numbering system) was a consistent finding in all cases of hereditary pancreatitis (<a href="/entry/167800">167800</a>) examined by <a href="#34" class="mim-tip-reference" title="Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D. <strong>Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.</strong> Nature Genet. 14: 141-145, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841182</a>] [<a href="https://doi.org/10.1038/ng1096-141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841182">Whitcomb et al. (1996)</a>--a total of 20 affected individuals and 6 obligate carriers in 5 kindreds. X-ray crystal structure analysis, molecular modeling, and protein digest data indicated that the arg117 residue is a trypsin-sensitive site. The authors suggested that cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841182" 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="Ferec, C., Raguenes, O., Salomon, R., Roche, C., Bernard, J. P., Guillot, M., Quere, I., Faure, C., Mercier, B., Audrezet, M. P., Guillausseau, P. J., Dupont, C., Munnich, A., Bignon, J. D., Le Bodic, L. <strong>Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.</strong> J. Med. Genet. 36: 228-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204851</a>]" pmid="10204851">Ferec et al. (1999)</a> detected this mutation in 4 of 8 families with hereditary pancreatitis caused by mutation in the PRSS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In most cases the R122H mutation results from a G-to-A (CGC to CAC) transition (365G-A), which most probably occurred as a spontaneous deamination of 5-methylcytosine to give thymine in the CpG dinucleotides on the opposite strand (<a href="#4" class="mim-tip-reference" title="Chen, J.-M., Ferec, C. <strong>Molecular basis of hereditary pancreatitis.</strong> Europ. J. Hum. Genet. 8: 473-479, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10909845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10909845</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10909845">Chen and Ferec, 2000</a>). <a href="#7" class="mim-tip-reference" title="Chen, J.-M., Raguenes, O., Ferec, C., Deprez, P. H., Verellen-Dumoulin, C. <strong>A CGC-to-CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. (Letter)</strong> J. Med. Genet. 37: e36 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073545</a>] [<a href="https://doi.org/10.1136/jmg.37.11.e36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073545">Chen et al. (2000)</a> identified a GC-to-AT (CGC to CAT) substitution (<a href="#0008">276000.0008</a>), which also resulted in an R122H mutation but clearly arose via a different genetic mechanism, namely, gene conversion. This theory was strongly supported by the presence of AT in the corresponding position of 2 homologous genes and a Chi-like sequence in the 3-prime vicinity of the mutation. This mutation would not be detected by the generally used screening method based on a specific restriction site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10909845+11073545" 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="#1" class="mim-tip-reference" title="Audrezet, M.-P., Chen, J.-M., Le Marechal, C., Ruszniewski, P., Robaszkiewicz, M., Raguenes, O., Quere, I., Scotet, V., Ferec, C. <strong>Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis.</strong> Europ. J. Hum. Genet. 10: 100-106, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938439</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11938439">Audrezet et al. (2002)</a> analyzed the entire coding sequence and exon/intron junctions of the PRSS1 gene by denaturing gradient gel electrophoresis (DGGE) analysis and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. The R122H missense mutation was found in a 42-year-old male patient who had suffered the disease from the age of 6 years, and with no family members reported to have pancreatitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11938439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Simon, P., Weiss, F. U., Zimmer, K. P., Rand, S., Brinkmann, B., Domschke, W., Lerch, M. M. <strong>Spontaneous and sporadic trypsinogen mutations in idiopathic pancreatitis. (Letter)</strong> JAMA 288: 2122 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12413370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12413370</a>] [<a href="https://doi.org/10.1001/jama.288.17.2122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12413370">Simon et al. (2002)</a> reported the trypsinogen mutation in 5 of 50 patients (10%) with idiopathic pancreatitis; all 5 had the R122H mutation. Patients with trypsinogen mutations were significantly younger at disease onset (mean age, 14 years) than the remaining cohort (38 years) and accounted for 35% of the patients younger than 25 years. At least 1 of the 5 patients could be confidently stated to have a de novo R122H mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12413370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among cases of chronic pancreatitis, mutations in arg122 and in neighboring amino acid residues have been found with unusually high frequency. Furthermore, the R122H mutation has been found worldwide and, as noted, was identified as a de novo mutation in a German patient by <a href="#27" class="mim-tip-reference" title="Simon, P., Weiss, F. U., Zimmer, K. P., Rand, S., Brinkmann, B., Domschke, W., Lerch, M. M. <strong>Spontaneous and sporadic trypsinogen mutations in idiopathic pancreatitis. (Letter)</strong> JAMA 288: 2122 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12413370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12413370</a>] [<a href="https://doi.org/10.1001/jama.288.17.2122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12413370">Simon et al. (2002)</a>. An R122C amino acid change (<a href="#0009">276000.0009</a>) had been found by 4 groups including their own, according to <a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a>. <a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> proposed that the high frequency of mutations in or close to arg122 causing chronic pancreatitis suggests that 'this sequence is particularly prone to mutations.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12413370+16791840" 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> rs111033566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033566;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/rs111033566?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=rs111033566" 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=rs111033566" 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=RCV000012652 OR RCV000763166 OR RCV001507089 OR RCV002463587 OR RCV003103713 OR RCV004754255" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012652, RCV000763166, RCV001507089, RCV002463587, RCV003103713, RCV004754255" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012652...</a>
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<p>In affected members and obligate carriers of a family originally reported by <a href="#21" class="mim-tip-reference" title="Robechek, P. J. <strong>Hereditary chronic relapsing pancreatitis: a clue to pancreatitis in general?</strong> Am. J. Surg. 113: 819-824, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6023921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6023921</a>] [<a href="https://doi.org/10.1016/0002-9610(67)90354-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6023921">Robechek (1967)</a> with hereditary pancreatitis (<a href="/entry/167800">167800</a>) believed to be due to hypertrophy of the sphincter of Oddi, <a href="#11" class="mim-tip-reference" title="Gorry, M. C., Gabbaizedeh, D., Furey, W., Gates, L. K., Jr., Preston, R. A., Aston, C. E., Zhang, Y., Ulrich, C., Ehrlich, G. D., Whitcomb, D. C. <strong>Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.</strong> Gastroenterology 113: 1063-1068, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9322498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9322498</a>] [<a href="https://doi.org/10.1053/gast.1997.v113.pm9322498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9322498">Gorry et al. (1997)</a> identified heterozygosity for an A-to-T transversion in exon 2 of the PRSS1 gene, resulting in an asn29-to-ile (N29I) substitution. Affected members of an unrelated family with hereditary pancreatitis, negative for the common R122H mutation in the PRSS1 gene (<a href="#0001">276000.0001</a>), were also found to have the N29I mutation, which was not identified in 188 unrelated control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6023921+9322498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated families in a study of 14 hereditary pancreatitis families, <a href="#10" class="mim-tip-reference" title="Ferec, C., Raguenes, O., Salomon, R., Roche, C., Bernard, J. P., Guillot, M., Quere, I., Faure, C., Mercier, B., Audrezet, M. P., Guillausseau, P. J., Dupont, C., Munnich, A., Bignon, J. D., Le Bodic, L. <strong>Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.</strong> J. Med. Genet. 36: 228-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204851</a>]" pmid="10204851">Ferec et al. (1999)</a> reported an A-to-T transversion at codon 29 resulting in the substitution of isoleucine for asparagine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204851" 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="Chen, J.-M., Ferec, C. <strong>Origin and implication of the hereditary pancreatitis-associated N21I mutation in the cationic trypsinogen gene.</strong> Hum. Genet. 106: 125-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982192</a>] [<a href="https://doi.org/10.1007/s004390051019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982192">Chen and Ferec (2000)</a> suggested that the N29I mutation most likely arose as a gene conversion event in which the functional anionic trypsinogen gene (PRSS2; <a href="/entry/601564">601564</a>) acted as the donor sequence. This hypothesis was supported by the unique presence of isoleucine at residue 29 of the anionic gene among the several highly homologous trypsinogen genes; a single unbroken tract of nucleotides of up to 113 bp flanking the I29 residue in the anionic trypsinogen gene; and the presence of a chi-like sequence in the 5-prime proximity and a palindromic sequence in the 3-prime vicinity of the N29I mutation. Furthermore, a multiple alignment of the partial amino acid sequence of vertebrate trypsins around residue 29 indicated that N29 and I29 may represent advantageously selected mutations of the 2 functional human trypsinogen genes in evolutionary history. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982192" 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>This mutation has been designated ASN21ILE in a different numbering system.</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">rs111033567 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033567;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=rs111033567" 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=rs111033567" 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=RCV000012653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012653</a>
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<p>In a study of 14 families with hereditary pancreatitis (<a href="/entry/167800">167800</a>), <a href="#10" class="mim-tip-reference" title="Ferec, C., Raguenes, O., Salomon, R., Roche, C., Bernard, J. P., Guillot, M., Quere, I., Faure, C., Mercier, B., Audrezet, M. P., Guillausseau, P. J., Dupont, C., Munnich, A., Bignon, J. D., Le Bodic, L. <strong>Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.</strong> J. Med. Genet. 36: 228-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204851</a>]" pmid="10204851">Ferec et al. (1999)</a> identified an A-to-G transition at codon 23 in the PRSS1 gene, resulting in a substitution of arginine for lysine, in 1 family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204851" 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">rs386134264 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134264;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=rs386134264" 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=rs386134264" 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=RCV000030382 OR RCV002054515 OR RCV002225271" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030382, RCV002054515, RCV002225271" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030382...</a>
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<p>In a single individual with hereditary pancreatitis (<a href="/entry/167800">167800</a>), <a href="#10" class="mim-tip-reference" title="Ferec, C., Raguenes, O., Salomon, R., Roche, C., Bernard, J. P., Guillot, M., Quere, I., Faure, C., Mercier, B., Audrezet, M. P., Guillausseau, P. J., Dupont, C., Munnich, A., Bignon, J. D., Le Bodic, L. <strong>Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.</strong> J. Med. Genet. 36: 228-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204851</a>]" pmid="10204851">Ferec et al. (1999)</a> reported a 3-bp deletion (TCC) at position -28 (from ATG). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204851" 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> rs111033564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033564;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/rs111033564?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=rs111033564" 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=rs111033564" 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=RCV000012655 OR RCV000757691 OR RCV001192438" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012655, RCV000757691, RCV001192438" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012655...</a>
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<p><a href="#31" class="mim-tip-reference" title="Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M. <strong>Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).</strong> Hum. Mutat. 23: 22-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14695529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14695529</a>] [<a href="https://doi.org/10.1002/humu.10285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14695529">Teich et al. (2004)</a> identified a glu79-to-lys (E79K; 235G-A) mutation of the PRSS1 gene in 3 European families affected by pancreatitis (<a href="/entry/167800">167800</a>). The index patient was a 57-year-old German woman who 6 years previously had developed recurrent diarrhea that was assumed to be of psychosomatic origin. Two years previously, she complained of permanently increased stool frequency, fatty stools, and the recurrent appearance of undigested nutrients in the stool. Ultrasound revealed calcifications in the pancreas and a dilated pancreatic duct. Pancreatic enzyme replacement therapy allowed her to regain weight and relieve her symptoms. Because of increasing obstruction of the bile duct, a duodenum-preserving pancreatic head resection was performed. A 68-year-old brother was similarly affected and both were heterozygous for the E79K mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14695529" 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="#31" class="mim-tip-reference" title="Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M. <strong>Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).</strong> Hum. Mutat. 23: 22-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14695529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14695529</a>] [<a href="https://doi.org/10.1002/humu.10285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14695529">Teich et al. (2004)</a> described peculiar characteristics of the E79K mutation. In vitro analysis of recombinant wildtype in mutant enzymes revealed that the catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor (PSTI; <a href="/entry/167790">167790</a>) was unaffected. Although the E79K mutation produced a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. In contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen PRSS2 (<a href="/entry/601564">601564</a>) 2-fold while the common pancreatitis-associated mutants R122H (<a href="#0001">276000.0001</a>) or N29I (<a href="#0002">276000.0002</a>), had no such effect. The observations not only suggested a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlighted the importance of interactions between the 2 major trypsinogen isoforms in the development of genetically determined chronic pancreatitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14695529" 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 PANCREATITIS, HEREDITARY</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> rs144422014 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144422014;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/rs144422014?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=rs144422014" 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=rs144422014" 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=RCV000012656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012656</a>
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<p>In a patient with chronic pancreatitis (<a href="/entry/167800">167800</a>), <a href="#32" class="mim-tip-reference" title="Teich, N., Nemoda, Z., Kohler, H., Heinritz, W., Mossner, J., Keim, V., Sahin-Toth, M. <strong>Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl.</strong> Hum. Mutat. 25: 343-347, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15776435[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/10.1002/humu.20148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776435">Teich et al. (2005)</a> identified a conversion event whereby at least 289 nucleotides in exon 2 and the subsequent intron of the PRSS1 gene were replaced with the paralogous sequence from the PRSS2 gene (<a href="/entry/601564">601564</a>), resulting in an 86A-T transversion and a 161A-G transition, which caused asn29-to-ile (N29I; <a href="#0002">276000.0002</a>) and asn54-to-ser (N54S) substitutions, respectively. The double-mutant cationic trypsinogen showed increased autocatalytic activation, which was solely due to the N29I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PANCREATITIS, HEREDITARY</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> rs111033565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033565;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/rs111033565?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=rs111033565" 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=rs111033565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606982 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606982;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=rs267606982" 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=rs267606982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In addition to the originally reported and frequently found R122H mutation due to a single-nucleotide substitution (<a href="#0001">276000.0001</a>), <a href="#7" class="mim-tip-reference" title="Chen, J.-M., Raguenes, O., Ferec, C., Deprez, P. H., Verellen-Dumoulin, C. <strong>A CGC-to-CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. (Letter)</strong> J. Med. Genet. 37: e36 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073545</a>] [<a href="https://doi.org/10.1136/jmg.37.11.e36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073545">Chen et al. (2000)</a> identified a GC-to-AT (CGC to CAT; 365-366GC-AT) substitution which also causes an R122H mutation and results in chronic pancreatitis (<a href="/entry/167800">167800</a>). <a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> interpreted this variant as an example of a gene conversion event, i.e., the substitution of genetic material from another gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11073545+16791840" 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> rs111033568 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033568;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/rs111033568?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=rs111033568" 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=rs111033568" 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=RCV000012658 OR RCV001530066 OR RCV004754256" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012658, RCV001530066, RCV004754256" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012658...</a>
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<p>Four independent groups (see review by <a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al., 2006</a>) found this mutation in arg122, R122C, resulting from a 364C-T transition in exon 3 of the PRSS1 gene in patients with hereditary pancreatitis (<a href="/entry/167800">167800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791840" 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=RCV000012659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012659</a>
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<p>In a study of a cohort of 34 families with hereditary pancreatitis (<a href="/entry/167800">167800</a>) but no known missense mutations in PRSS1, PRSS2, SPINK1, or CFTR, <a href="#17" class="mim-tip-reference" title="Le Marechal, C., Masson, E., Chen, J.-M., Morel, F., Ruszniewski, P., Levy, P., Ferec, C. <strong>Hereditary pancreatitis caused by triplication of the trypsinogen locus.</strong> Nature Genet. 38: 1372-1374, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17072318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17072318</a>] [<a href="https://doi.org/10.1038/ng1904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17072318">Le Marechal et al. (2006)</a> identified triplication of the PRSS1 gene. Some unaffected members of the family were heterozygous for the same triplication, indicating a high but incomplete penetrance of the hereditary pancreatitis caused by the triplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17072318" 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="Chauvin, A., Chen, J.-M., Quemener, S., Masson, E., Kehrer-Sawatzki, H., Ohmle, B., Cooper, D. N., Le Marechal, C., Ferec, C. <strong>Elucidation of the complex structure and origin of the human trypsinogen locus triplication.</strong> Hum. Molec. Genet. 18: 3605-3614, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19584086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19584086</a>] [<a href="https://doi.org/10.1093/hmg/ddp308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19584086">Chauvin et al. (2009)</a> characterized the triplication copy number mutation in the PRSS1 gene and found it to be part of a complex rearrangement that also contains a triplicated 137-kb segment and 21-bp sequence tract. The triplication allele constitutes a gain of 2 tandemly arranged composite duplication blocks, each comprising a copy of the 605-kb segment, a copy of the inverted 137-kb segment, and a copy of the inverted 21-bp sequence tract. All triplications and duplications identified were found to arise from a common founder chromosome. The authors proposed a 2-step process for the generation of the triplication copy number mutation. <a href="#2" class="mim-tip-reference" title="Chauvin, A., Chen, J.-M., Quemener, S., Masson, E., Kehrer-Sawatzki, H., Ohmle, B., Cooper, D. N., Le Marechal, C., Ferec, C. <strong>Elucidation of the complex structure and origin of the human trypsinogen locus triplication.</strong> Hum. Molec. Genet. 18: 3605-3614, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19584086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19584086</a>] [<a href="https://doi.org/10.1093/hmg/ddp308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19584086">Chauvin et al. (2009)</a> hypothesized that many human germline copy number variants may arise through replication-based mechanisms during the premeiotic mitotic divisions of germ cells. The low copy repeats generated could then serve to promote nonallelic homologous recombination (NAHR) during meiosis, giving rise to amplified DNA sequences, which could themselves predispose to further recombination events during both mitosis and meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19584086" 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> rs199422123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422123;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/rs199422123?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=rs199422123" 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=rs199422123" 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=RCV000012660 OR RCV001753414 OR RCV003234902" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012660, RCV001753414, RCV003234902" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012660...</a>
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<p>This variant, formerly titled HEREDITARY PANCREATITIS, has been reclassified based on the findings of <a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20452997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with hereditary pancreatitis (<a href="/entry/167800">167800</a>), <a href="#9" class="mim-tip-reference" title="Felderbauer, P., Schnekenburger, J., Lebert, R., Bulut, K., Parry, M., Meister, T., Schick, V., Schmitz, F., Domschke, W., Schmidt, W. E. <strong>A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site.</strong> J. Med. Genet. 45: 507-512, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511571</a>] [<a href="https://doi.org/10.1136/jmg.2007.056481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511571">Felderbauer et al. (2008)</a> identified a heterozygous G-to-A transition in exon 3 of the PRSS1 gene, resulting in an ala121-to-thr (A121T) substitution. The proband had relatively late disease onset in his thirties, and family history indicated reduced penetrance. In vitro functional expression studies showed that the mutant protein resulted in increased digestion by trypsin (more than 80% compared to wildtype PRSS1) that was calcium-dependent. The findings were consistent with a increased autodegradation and a loss of function mechanism, which was opposite to that observed with the common R122H mutation (<a href="#0001">276000.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18511571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> presented evidence that the A121T variant is functionally innocuous and not a cause of pancreatitis. The authors noted that only the index patient in the report of <a href="#9" class="mim-tip-reference" title="Felderbauer, P., Schnekenburger, J., Lebert, R., Bulut, K., Parry, M., Meister, T., Schick, V., Schmitz, F., Domschke, W., Schmidt, W. E. <strong>A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site.</strong> J. Med. Genet. 45: 507-512, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511571</a>] [<a href="https://doi.org/10.1136/jmg.2007.056481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511571">Felderbauer et al. (2008)</a> carried the A121T variant and suffered from chronic pancreatitis. The patient's brother and first cousin, who both carried the variant, had cholelithiasis, and his niece and her mother were asymptomatic carriers. Functional expression studies by <a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> indicated that autoactivation of trypsinogens by the A121T variant was similar to wildtype with equal enzyme kinetics. <a href="#28" class="mim-tip-reference" title="Szmola, R., Sahin-Toth, M. <strong>Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.</strong> J. Med. Genet. 47: 348-350, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20452997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20452997</a>] [<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20452997">Szmola and Sahin-Toth (2010)</a> suggested that the variant may have been assigned clinical relevance based on a perceived analogy with the neighboring disease-causing R122H mutations (<a href="#0001">276000.0001</a> and <a href="#0008">276000.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18511571+20452997" 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> rs387906698 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906698;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/rs387906698?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=rs387906698" 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=rs387906698" 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=RCV000022814 OR RCV004557257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022814, RCV004557257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022814...</a>
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<p><a href="#33" class="mim-tip-reference" title="Teich, N., Rosendahl, J., Toth, M., Mossner, J., Sahin-Toth, M. <strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong> Hum. Mutat. 27: 721-730, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>] [<a href="https://doi.org/10.1002/humu.20343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791840">Teich et al. (2006)</a> reported that the 346C-T transition in exon 3 of the PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been identified by 4 independent groups in Turkish, German, and Thai families with hereditary pancreatitis (<a href="/entry/167800">167800</a>) and in 2 unrelated French patients with pancreatitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 11-year-old German girl with hereditary pancreatitis, originally reported by <a href="#30" class="mim-tip-reference" title="Teich, N., Bauer, N., Mossner, J., Keim, V. <strong>Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants.</strong> Am. J. Gastroent. 97: 341-346, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11866271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11866271</a>] [<a href="https://doi.org/10.1111/j.1572-0241.2002.05467.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11866271">Teich et al. (2002)</a>, <a href="#16" class="mim-tip-reference" title="Kereszturi, E., Szmola, R., Kukor, Z., Simon, P., Weiss, F. U., Lerch, M. M., Sahin-Toth, M. <strong>Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism.</strong> Hum. Mutat. 30: 575-582, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19191323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19191323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19191323[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/10.1002/humu.20853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19191323">Kereszturi et al. (2009)</a> showed that trypsinogen misfolding is the likely disease mechanism. The R116C substitution occurs in a surface loop that is highly sensitive to autolytic cleavage. In vitro functional expression studies showed that the R116C mutation resulted in misfolding of the protein, but residual amounts of properly folded protein showed normal activation, catalytic properties, and degradation. Expression of the mutant protein in HEK 293T cells showed decreased secretion compared to wildtype, suggesting that the unpaired cysteine residue at codon 116 interferes with proper protein folding, resulting in the mutant protein being retained inside the cell. Biochemical evidence indicated activation of the unfolded protein response, although there was no evidence of increased caspase-3 (CASP3; <a href="/entry/600636">600636</a>) activity. The R116C mutation was also found in the girl's 57-year-old affected maternal grandfather and her 38-year-old unaffected mother, indicating incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19191323+11866271" 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>Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis.</strong>
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Europ. J. Hum. Genet. 10: 100-106, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938439</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11938439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Elucidation of the complex structure and origin of the human trypsinogen locus triplication.</strong>
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Hum. Molec. Genet. 18: 3605-3614, 2009.
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[<a href="https://doi.org/10.1093/hmg/ddp308" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390051019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390100580" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0508-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9610(67)90354-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.272.5269.1755" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1999.1565" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.2000.3797" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ecl.2006.02.002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.288.17.2122" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.072751" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/18.6.1631" target="_blank">Full Text</a>]
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<strong>Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11866271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11866271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11866271" 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/10.1111/j.1572-0241.2002.05467.x" target="_blank">Full Text</a>]
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Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14695529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14695529</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14695529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10285" target="_blank">Full Text</a>]
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Teich, N., Nemoda, Z., Kohler, H., Heinritz, W., Mossner, J., Keim, V., Sahin-Toth, M.
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<strong>Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15776435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20148" target="_blank">Full Text</a>]
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<strong>Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20343" target="_blank">Full Text</a>]
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Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D.
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[<a href="https://doi.org/10.1038/ng1096-141" target="_blank">Full Text</a>]
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<strong>Cloning of the cDNA encoding human brain trypsinogen and characterization of its product.</strong>
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[<a href="https://doi.org/10.1016/0378-1119(93)90460-k" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 01/14/2021
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Cassandra L. Kniffin - updated : 1/19/2011<br>George E. Tiller - updated : 7/8/2010<br>Cassandra L. Kniffin - updated : 6/3/2010<br>Cassandra L. Kniffin - updated : 2/9/2009<br>Cassandra L. Kniffin - updated : 9/18/2008<br>Marla J. F. O'Neill - updated : 3/1/2007<br>Victor A. McKusick - updated : 1/5/2007<br>Victor A. McKusick - updated : 8/24/2006<br>Victor A. McKusick - updated : 4/28/2005<br>Victor A. McKusick - updated : 2/3/2004<br>Victor A. McKusick - updated : 12/27/2002<br>Michael B. Petersen - updated : 10/8/2002<br>Victor A. McKusick - updated : 10/12/2001<br>Victor A. McKusick - updated : 3/27/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Michael J. Wright - updated : 11/3/1999<br>Victor A. McKusick - updated : 1/20/1998
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Victor A. McKusick : 6/4/1986
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mgross : 01/14/2021
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carol : 03/29/2016<br>alopez : 3/28/2016<br>carol : 1/29/2015<br>mgross : 10/4/2013<br>carol : 6/16/2011<br>wwang : 2/4/2011<br>ckniffin : 1/19/2011<br>mgross : 9/29/2010<br>wwang : 7/22/2010<br>terry : 7/8/2010<br>wwang : 6/7/2010<br>ckniffin : 6/3/2010<br>terry : 6/3/2009<br>wwang : 4/6/2009<br>ckniffin : 2/9/2009<br>terry : 2/2/2009<br>wwang : 10/2/2008<br>ckniffin : 9/18/2008<br>terry : 8/26/2008<br>carol : 3/1/2007<br>carol : 3/1/2007<br>carol : 1/9/2007<br>carol : 1/9/2007<br>terry : 1/5/2007<br>alopez : 9/5/2006<br>terry : 8/24/2006<br>alopez : 5/31/2006<br>tkritzer : 5/10/2005<br>terry : 4/28/2005<br>terry : 2/2/2005<br>joanna : 3/17/2004<br>cwells : 2/6/2004<br>terry : 2/3/2004<br>cwells : 12/31/2002<br>terry : 12/27/2002<br>cwells : 10/8/2002<br>carol : 1/28/2002<br>carol : 10/29/2001<br>mcapotos : 10/12/2001<br>carol : 4/2/2001<br>mcapotos : 3/27/2001<br>terry : 3/27/2001<br>terry : 3/15/2001<br>mcapotos : 1/4/2001<br>mcapotos : 1/3/2001<br>terry : 12/19/2000<br>alopez : 2/29/2000<br>terry : 2/17/2000<br>mgross : 1/11/2000<br>terry : 12/20/1999<br>alopez : 11/10/1999<br>terry : 11/3/1999<br>dkim : 9/9/1998<br>mark : 1/22/1998<br>terry : 1/20/1998<br>terry : 9/15/1997<br>terry : 12/12/1996<br>terry : 12/4/1996<br>jamie : 10/23/1996<br>jamie : 10/18/1996<br>jamie : 10/16/1996<br>mark : 9/30/1996<br>mark : 9/30/1996<br>terry : 9/26/1996<br>mark : 8/18/1996<br>terry : 8/16/1996<br>mark : 7/9/1995<br>davew : 7/6/1994<br>carol : 4/18/1994<br>mimadm : 3/12/1994<br>supermim : 3/17/1992
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<span class="mim-font">
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<strong>*</strong> 276000
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PROTEASE, SERINE, 1; PRSS1
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<em>Alternative titles; symbols</em>
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TRYPSINOGEN 1; TRY1<br />
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TRYPSINOGEN, CATIONIC
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Other entities represented in this entry:
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TRYPSIN 1, INCLUDED
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<strong><em>HGNC Approved Gene Symbol: PRSS1</em></strong>
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<strong>SNOMEDCT:</strong> 235956004, 68072000;
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Cytogenetic location: 7q34
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:142,749,472-142,753,072 </span>
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</em>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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7q34
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Pancreatitis, hereditary
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167800
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Human pancreatic juice contains 3 isoforms of trypsinogen. On the basis of their relative electrophoretic mobility, these are commonly referred to as cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2; 601564), and mesotrypsinogen (PRSS3; 613578). Normally, cationic trypsinogen represents approximately two-thirds of total trypsinogen, while anionic trypsinogen makes up approximately one-third. Mesotrypsinogen is a minor species, accounting for less than 5% of trypsinogens or 0.5% of pancreatic juice proteins (Scheele et al., 1981; Rinderknecht et al. (1984); summary by Teich et al., 2004). </p><p>Trypsin (EC 3.4.21.4) is a member of the pancreatic family of serine proteases.</p>
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<strong>Cloning and Expression</strong>
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<p>MacDonald et al. (1982) reported nucleotide sequences of cDNAs representing 2 pancreatic rat trypsinogens. </p><p>Emi et al. (1986) isolated cDNA clones for 2 major human trypsinogen isozymes from a pancreatic cDNA library. The deduced amino acid sequences had 89% homology and the same number of amino acids (247), including a 15-amino acid signal peptide and an 8-amino acid activation peptide. </p><p>Rowen et al. (1996) found that 2 of 3 pancreatically expressed trypsinogen cDNAs correspond to trypsinogen genes embedded in the beta T-cell receptor (TCRB; see 186930) cluster of genes mapping to 7q35. T4 was denoted trypsinogen-1 and T8 was denoted trypsinogen-2 (601564). The third pancreatic cDNA, identified independently as trypsinogen-3 (Tani et al., 1990) and -4 (Wiegand et al., 1993), is distinct from the third apparently functional trypsinogen gene (T6) in the TCRB locus but related to the other pancreatic trypsinogens. Rowen et al. (1996) noted that the intercalation of the trypsinogen genes in the TCRB locus is conserved in mouse and chicken, suggesting shared functional or regulatory constraints, as has been postulated for genes in the major histocompatibility complex (such as class I, II, and III genes) that share similar long-term organizational relationships. </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>By alignment of pancreatic trypsinogen cDNAs with the germline sequences, Rowen et al. (1996) showed that the trypsinogen genes contain 5 exons that span approximately 3.6 kb. Further analyses revealed 2 trypsinogen pseudogenes and 1 relic trypsinogen gene at the 5-prime end of the sequence, all in inverted transcriptional orientation. They denoted 8 trypsinogen genes T1 through T8 from 5-prime to 3-prime. </p>
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<strong>Mapping</strong>
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<p>Using a rat cDNA probe, Honey et al. (1984, 1984) found that a 3.8-kb DNA fragment containing human trypsin-1 gene sequences cosegregated with chromosome 7, and assigned the gene further to 7q22-7qter by study of hybrids with a deletion of this segment. The trypsin gene is on mouse chromosome 6 (Honey et al., 1984). Carboxypeptidase A (114850) and trypsin are a syntenic pair conserved in mouse and man. </p><p>Using Southern blot analysis of human genomic DNA with a cloned cDNA as probe, Emi et al. (1986) showed that the human trypsinogen genes constitute a family of more than 10, some of which may be pseudogenes or may be expressed in other stages of development. </p><p>Rowen et al. (1996) mapped the gene corresponding to the third pancreatic trypsinogen cDNA by fluorescence in situ hybridization. They used a cosmid clone containing 3 trypsinogen genes. Strong hybridization to chromosome 7 and weaker hybridization to chromosome 9 were observed. They isolated and partially sequenced 4 cosmid clones from the chromosome 9 region. They found that the region represents a duplication and translocation of a DNA segment from the 3-prime end of the TCRB locus that includes at least 7 V(beta) elements and a functional trypsinogen gene denoted T9 (PRSS3; 613578). </p><p>Rowen et al. (1996) found that there are 8 trypsinogen genes embedded in the beta T-cell receptor locus or cluster of genes (TCRB; see 186930) mapping to 7q35. In the 685-kb DNA segment that they sequenced they found 5 tandemly arrayed 10-kb locus-specific repeats (homology units) at the 3-prime end of the locus. These repeats exhibited 90 to 91% overall nucleotide similarity, and embedded within each is a trypsinogen gene. Since hereditary pancreatitis (167800) had been mapped rather precisely to 7q35 and since a defect in the trypsinogen gene has been identified in hereditary pancreatitis, the assignment of the trypsinogen gene can be refined from 7q32-qter to 7q35. </p>
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<strong>Molecular Genetics</strong>
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<p>Whitcomb et al. (1996) stated that the high degree of DNA sequence homology (more than 91%) present among this cluster of 5 trypsinogen genes identified by Rowen et al. (1996) demanded that highly specific sequence analysis strategies be developed for mutation screening in families with hereditary pancreatitis (167800). This was necessary to ensure that each sequencing run contained only the 2 alleles corresponding to a single gene, thereby permitting detection of heterozygotes in this autosomal dominant disorder, and not a dozen or more alleles from multiple related trypsinogen-like genes, which would make detection of heterozygotes nearly impossible. In a family with hereditary pancreatitis, Whitcomb et al. (1996) found that affected individuals had a single G-to-A transition mutation in the third exon of cationic trypsinogen (276000.0001). This mutation was predicted to result in an arg105-to-his substitution in the trypsin gene (residue number 122 in the more common trypsinogen number system; the residue has also been listed as 117; 276000.0001). Subsequently, the same mutation was found in a total of 5 different hereditary pancreatitis kindreds (4 from the U.S. and 1 from Italy) containing a total of 20 affected individuals and 6 obligate carriers. The mutation was found in none of the obligate unaffected members (individuals who married into the family). Subsequent haplotyping revealed that all 4 of the American families displayed the same high risk haplotype over a 4-cM region encompassing 7 STR markers, confirming the likelihood that these kindreds shared a common ancestor, although no link could be found through 8 generations. A fifth family from Italy displayed a unique haplotype indicating that the same mutation had occurred on at least 2 occasions. The G-to-A mutation at codon 122 created a novel enzyme recognition site for AflIII which provided a facile means to screen for the mutation. As with the obligate unaffected members of the pancreatitis kindreds, none of 140 controls possessed the G-to-A mutation as assayed by the lack of AflIII digestion of the amplified exonic DNA. </p><p>Ferec et al. (1999) studied 14 families with hereditary pancreatitis and found mutations in the PRSS1 gene in 8 families. In 4 of these families, the mutation (R122H; 276000.0001) had been described by Whitcomb et al. (1996). Three mutations were described in 4 other families (276000.0002, 276000.0003, 276000.0005). </p><p>Sahin-Toth et al. (1999) studied the roles of the 2 most frequent PRSS1 mutations in hereditary pancreatitis, R122H and N29I (276000.0002). They stated that the R122H mutation is believed to cause pancreatitis by eliminating an essential autolytic cleavage site in trypsin, thereby rendering the protease resistant to inactivation through autolysis. Sahin-Toth et al. (1999) demonstrated that the R122H mutation also significantly inhibited autocatalytic trypsinogen breakdown under Ca(2+)-free conditions and stabilized the zymogen form of rat trypsin. Taken together with findings demonstrating that the N29I mutation stabilized rat trypsinogen against autoactivation and consequent autocatalytic degradation, the observations suggested a unifying molecular pathomechanism for hereditary pancreatitis in which zymogen stabilization plays a central role. </p><p>Sahin-Toth and Toth (2000) demonstrated that the R122H and N29I mutations significantly enhance autoactivation of human cationic trypsinogen in vitro, in a manner that correlates with the severity of clinical symptoms in hereditary pancreatitis. In addition, the R122H mutation inhibited autocatalytic inactivation of trypsin, while the N29I mutation had no such effect. Thus, increased trypsinogen activation in the pancreas is presumably the common initiating step in both forms of hereditary pancreatitis, whereas trypsin stabilization may also contribute to hereditary pancreatitis associated with the R122H mutation. </p><p>Chen et al. (2001) reviewed aspects of the molecular evolution and normal physiology of trypsinogen revealed by studies of PRSS1 in pancreatitis. First, the activation peptide of trypsinogen is under strong selection pressure to minimize autoactivation in higher vertebrates. Second, the R122 primary autolysis site (276000.0001) has further evolved in mammalian trypsinogens. Third, evolutionary divergence from threonine to asparagine at residue 29 in human cationic trypsinogen provides additional advantage. Accordingly, Chen et al. (2001) tentatively assigned, in human cationic trypsinogen, the strongly selected activation peptide as the first line and the R122 autolysis site as the second line of the built-in defensive mechanisms against premature trypsin activation within the pancreas, and the positively selected asparagine at residue 29 as an 'amplifier' to the R122 'fail-safe' mechanism. </p><p>Gene conversion--the substitution of genetic material from one gene to another--in most cases takes place between a normal gene and its pseudogene. Teich et al. (2005) reported the occurrence of disease-associated gene conversion between 2 functional genes. They analyzed PRSS1 in 1,106 patients with chronic pancreatitis and in 1 patient identified a novel conversion event affecting exon 2 and the subsequent intron. The conversion replaced at least 289 nucleotides with the paralogous sequence from the PRSS2 gene and resulted in asn29-to-ile (N29I; 276000.0002) and asn54-to-ser (N54S) substitutions (276000.0007). Analysis of the recombinant N29I/N54S double-mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N29I mutation. </p><p>Teich et al. (2006) interpreted the 365_366GC-AT R122H variant (276000.0008) as an example of a gene conversion event. In most such cases, the donor gene is a duplicated pseudogene which has accumulated mutations over time. However, there is evidence that gene conversion can occur between 2 functional paralogous trypsinogen genes and cause chronic pancreatitis. Trypsinogen genes are tandemly repeated within the T-cell receptor beta locus (TCRB; see 186930) on 7q35. This is a hotspot for gene conversion events to generate a broad variety of TCR-beta genes. Therefore, conversion mutation within the interpolated trypsinogen gene family are very likely to occur. </p><p>Teich et al. (2006) reviewed current information on trypsinogen mutations and their role in pancreatic diseases. They pointed out that, although the clinical presentation is highly variable, most affected mutation carriers have relatively mild disease. Teich et al. (2006) noted that, in addition to R122 mutations, pancreatitis-producing mutations had also been identified in the neighboring residues ala121 and val123. </p><p>Le Marechal et al. (2006) reviewed observations suggesting that trypsinogen may be sensitive to a gene dosage effect. They noted that the R122H mutation (276000.0001) and other pancreatitis-causing PRSS1 missense mutations show by in vitro functional analysis an increase in trypsin activity (see review by Sahin-Toth, 2006). On the other hand, an N34S variation (167790.0001) in the SPINK1 gene and rare splicing and frameshifting mutations in that gene have been detected in individuals with chronic pancreatitis. SPINK1 encodes trypsin's physiologic inhibitor, the physiologic function of which appears to be the prevention of the trypsin-driven digestive enzyme activation cascade. Loss-of-function mutations in PRSS1 (Chen et al., 2003) and a degradation-sensitive variant (G191R; 601564.0001) in the PRSS2 gene seem to confer protection against the disease. Le Marechal et al. (2006) surmised that an increased copy number of the PRSS1 gene at 7q34 might account for some of the families with hereditary pancreatitis without a known causative mutation. They studied a well-characterized cohort of 34 French families with hereditary pancreatitis (defined as 3 or more affected family members involving at least 2 generations) who did not carry any causative point mutations in the PRSS1, PRSS2, SPINK1, and CFTR genes. Analysis of 1 affected individual per family suggested that the PRSS1 locus was triplicated, and this was confirmed in 5 of the analyzed families. Use of walking quantitative fluorescent multiplex PCR showed that the triplication extended approximately 605 kb and included all members of the trypsinogen gene family on chromosome 7. The size of the triplicated segment seemed to be the same in all carriers. Affected individuals in these families shared an identical haplotype that extended approximately 1,100 kb telomeric to the PRSS1 locus, suggesting that the triplication represents an identical-by-descent mutation. </p><p>In all 6 affected members of a French family with chronic pancreatitis, Masson et al. (2008) identified the presence of a heterozygous PRSS1/PRSS2 hybrid gene. Quantitative fluorescent multiplex PCR and RT-PCR revealed duplication of exons 3 to 5 of PRSS1, and further analysis indicated that a nonallelic homologous recombination event resulted in the generation of a hybrid gene containing exons 1 and 2 from PRSS2 and exons 3 to 5 from PRSS1. This hybrid gene was predicted to encode a zymogen identical to a gene conversion-derived mutant cationic trypsinogen containing the N29I (276000.0002) and N54S (276000.0007) mutations. Masson et al. (2008) concluded that this hybrid gene caused the disease through an inherent double gain-of-function effect, acting simultaneously through an increased copy number effect and the N29I mutation. </p><p>Szmola and Sahin-Toth (2010) presented evidence that the A121T variant (276000.0011) is functionally innocuous and not a cause of pancreatitis. The authors noted that only the index patient in the report of Felderbauer et al. (2008) carried the A121T variant and suffered from chronic pancreatitis. The patient's brother and first cousin, who both carried the variant, had cholelithiasis, and his niece and her mother were asymptomatic carriers. Functional expression studies by Szmola and Sahin-Toth (2010) indicated that autoactivation of trypsinogens by the A121T variant was similar to wildtype with equal enzyme kinetics. Szmola and Sahin-Toth (2010) suggested that the variant may have been assigned clinical relevance based on a perceived analogy with the neighboring disease-causing R122H change (276000.0001 and 276000.0008). </p>
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</span>
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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>Gui et al. (2020) found that transgenic expression of full-length human PRSS1 with the R122H mutation in mice caused severe acute pancreatitis (AP) upon stimulation with cerulein. Cerulein induced mild AP in wildtype mice, with the mice recovering fully in a few days. In R122H transgenic mice, cerulein-induced AP failed to resolve and led to progressive pancreatic damage and activation of cellular stress signaling, resulting in chronic pancreatitis (CP) that resembled human hereditary pancreatitis caused by PRSS1 mutations. Human PRSS1 with the R122H mutation sensitized transgenic mice to development of cerulein-induced AP more severely than wildtype human PRSS1, because R122H was a gain-of-function mutation that increased trypsin activity. Treatment of R122H transgenic mice with trypsin inhibitors protected the pancreas from CP, and the anticoagulant dabigatran nearly abolished progression of CP. Anticoagulation and trypsin inhibition synergistically improved pancreatitis, as targeting both trypsin and coagulation pathways was required for effective pancreatitis therapy in mice. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</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>Rowen et al. (1996) stated that the apparently functional T6 gene is deleted in a common insertion-deletion polymorphism; if the gene is functional, its function is apparently not essential. </p>
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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>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 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 PANCREATITIS, HEREDITARY</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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PRSS1, ARG122HIS, 365G-A
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<br />
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SNP: rs111033565,
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gnomAD: rs111033565,
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ClinVar: RCV000012651, RCV000487005, RCV003944816
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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>The arg122-to-his mutation (R122H; previously designated ARG117HIS, or R117H, by the chymotrypsin numbering system) was a consistent finding in all cases of hereditary pancreatitis (167800) examined by Whitcomb et al. (1996)--a total of 20 affected individuals and 6 obligate carriers in 5 kindreds. X-ray crystal structure analysis, molecular modeling, and protein digest data indicated that the arg117 residue is a trypsin-sensitive site. The authors suggested that cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis. </p><p>Ferec et al. (1999) detected this mutation in 4 of 8 families with hereditary pancreatitis caused by mutation in the PRSS1 gene. </p><p>In most cases the R122H mutation results from a G-to-A (CGC to CAC) transition (365G-A), which most probably occurred as a spontaneous deamination of 5-methylcytosine to give thymine in the CpG dinucleotides on the opposite strand (Chen and Ferec, 2000). Chen et al. (2000) identified a GC-to-AT (CGC to CAT) substitution (276000.0008), which also resulted in an R122H mutation but clearly arose via a different genetic mechanism, namely, gene conversion. This theory was strongly supported by the presence of AT in the corresponding position of 2 homologous genes and a Chi-like sequence in the 3-prime vicinity of the mutation. This mutation would not be detected by the generally used screening method based on a specific restriction site. </p><p>Audrezet et al. (2002) analyzed the entire coding sequence and exon/intron junctions of the PRSS1 gene by denaturing gradient gel electrophoresis (DGGE) analysis and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. The R122H missense mutation was found in a 42-year-old male patient who had suffered the disease from the age of 6 years, and with no family members reported to have pancreatitis. </p><p>Simon et al. (2002) reported the trypsinogen mutation in 5 of 50 patients (10%) with idiopathic pancreatitis; all 5 had the R122H mutation. Patients with trypsinogen mutations were significantly younger at disease onset (mean age, 14 years) than the remaining cohort (38 years) and accounted for 35% of the patients younger than 25 years. At least 1 of the 5 patients could be confidently stated to have a de novo R122H mutation. </p><p>Among cases of chronic pancreatitis, mutations in arg122 and in neighboring amino acid residues have been found with unusually high frequency. Furthermore, the R122H mutation has been found worldwide and, as noted, was identified as a de novo mutation in a German patient by Simon et al. (2002). An R122C amino acid change (276000.0009) had been found by 4 groups including their own, according to Teich et al. (2006). Teich et al. (2006) proposed that the high frequency of mutations in or close to arg122 causing chronic pancreatitis suggests that 'this sequence is particularly prone to mutations.' </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 PANCREATITIS, HEREDITARY</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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PRSS1, ASN29ILE
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<br />
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SNP: rs111033566,
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gnomAD: rs111033566,
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ClinVar: RCV000012652, RCV000763166, RCV001507089, RCV002463587, RCV003103713, RCV004754255
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members and obligate carriers of a family originally reported by Robechek (1967) with hereditary pancreatitis (167800) believed to be due to hypertrophy of the sphincter of Oddi, Gorry et al. (1997) identified heterozygosity for an A-to-T transversion in exon 2 of the PRSS1 gene, resulting in an asn29-to-ile (N29I) substitution. Affected members of an unrelated family with hereditary pancreatitis, negative for the common R122H mutation in the PRSS1 gene (276000.0001), were also found to have the N29I mutation, which was not identified in 188 unrelated control chromosomes. </p><p>In 2 unrelated families in a study of 14 hereditary pancreatitis families, Ferec et al. (1999) reported an A-to-T transversion at codon 29 resulting in the substitution of isoleucine for asparagine. </p><p>Chen and Ferec (2000) suggested that the N29I mutation most likely arose as a gene conversion event in which the functional anionic trypsinogen gene (PRSS2; 601564) acted as the donor sequence. This hypothesis was supported by the unique presence of isoleucine at residue 29 of the anionic gene among the several highly homologous trypsinogen genes; a single unbroken tract of nucleotides of up to 113 bp flanking the I29 residue in the anionic trypsinogen gene; and the presence of a chi-like sequence in the 5-prime proximity and a palindromic sequence in the 3-prime vicinity of the N29I mutation. Furthermore, a multiple alignment of the partial amino acid sequence of vertebrate trypsins around residue 29 indicated that N29 and I29 may represent advantageously selected mutations of the 2 functional human trypsinogen genes in evolutionary history. </p><p>This mutation has been designated ASN21ILE in a different numbering system.</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 PANCREATITIS, HEREDITARY</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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PRSS1, LYS23ARG
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<br />
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SNP: rs111033567,
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ClinVar: RCV000012653
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a study of 14 families with hereditary pancreatitis (167800), Ferec et al. (1999) identified an A-to-G transition at codon 23 in the PRSS1 gene, resulting in a substitution of arginine for lysine, in 1 family. </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-text-font">
|
|
<strong>.0004 MOVED TO 276000.0002</strong>
|
|
</span>
|
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</h4>
|
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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 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRSS1, 3-BP DEL
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|
|
|
<br />
|
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|
|
SNP: rs386134264,
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|
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|
|
ClinVar: RCV000030382, RCV002054515, RCV002225271
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|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single individual with hereditary pancreatitis (167800), Ferec et al. (1999) reported a 3-bp deletion (TCC) at position -28 (from ATG). </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>.0006 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRSS1, GLU79LYS
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|
|
|
<br />
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|
|
SNP: rs111033564,
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|
|
gnomAD: rs111033564,
|
|
|
|
|
|
ClinVar: RCV000012655, RCV000757691, RCV001192438
|
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|
|
|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>Teich et al. (2004) identified a glu79-to-lys (E79K; 235G-A) mutation of the PRSS1 gene in 3 European families affected by pancreatitis (167800). The index patient was a 57-year-old German woman who 6 years previously had developed recurrent diarrhea that was assumed to be of psychosomatic origin. Two years previously, she complained of permanently increased stool frequency, fatty stools, and the recurrent appearance of undigested nutrients in the stool. Ultrasound revealed calcifications in the pancreas and a dilated pancreatic duct. Pancreatic enzyme replacement therapy allowed her to regain weight and relieve her symptoms. Because of increasing obstruction of the bile duct, a duodenum-preserving pancreatic head resection was performed. A 68-year-old brother was similarly affected and both were heterozygous for the E79K mutation. </p><p>Teich et al. (2004) described peculiar characteristics of the E79K mutation. In vitro analysis of recombinant wildtype in mutant enzymes revealed that the catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor (PSTI; 167790) was unaffected. Although the E79K mutation produced a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. In contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen PRSS2 (601564) 2-fold while the common pancreatitis-associated mutants R122H (276000.0001) or N29I (276000.0002), had no such effect. The observations not only suggested a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlighted the importance of interactions between the 2 major trypsinogen isoforms in the development of genetically determined chronic pancreatitis. </p>
|
|
</span>
|
|
</div>
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|
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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>.0007 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
PRSS1, ASN54SER
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<br />
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|
|
SNP: rs144422014,
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|
|
gnomAD: rs144422014,
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|
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ClinVar: RCV000012656
|
|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with chronic pancreatitis (167800), Teich et al. (2005) identified a conversion event whereby at least 289 nucleotides in exon 2 and the subsequent intron of the PRSS1 gene were replaced with the paralogous sequence from the PRSS2 gene (601564), resulting in an 86A-T transversion and a 161A-G transition, which caused asn29-to-ile (N29I; 276000.0002) and asn54-to-ser (N54S) substitutions, respectively. The double-mutant cationic trypsinogen showed increased autocatalytic activation, which was solely due to the N29I 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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRSS1, ARG122HIS, 365GC-AT
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033565, rs267606982,
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|
|
|
|
|
gnomAD: rs111033565,
|
|
|
|
|
|
ClinVar: RCV000012657
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|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In addition to the originally reported and frequently found R122H mutation due to a single-nucleotide substitution (276000.0001), Chen et al. (2000) identified a GC-to-AT (CGC to CAT; 365-366GC-AT) substitution which also causes an R122H mutation and results in chronic pancreatitis (167800). Teich et al. (2006) interpreted this variant as an example of a gene conversion event, i.e., the substitution of genetic material from another gene. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
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PRSS1, ARG122CYS
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|
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|
<br />
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|
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SNP: rs111033568,
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|
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gnomAD: rs111033568,
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|
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ClinVar: RCV000012658, RCV001530066, RCV004754256
|
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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>Four independent groups (see review by Teich et al., 2006) found this mutation in arg122, R122C, resulting from a 364C-T transition in exon 3 of the PRSS1 gene in patients with hereditary pancreatitis (167800). </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PANCREATITIS, HEREDITARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
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PRSS1, TRIPLICATION
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<br />
|
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|
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ClinVar: RCV000012659
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a study of a cohort of 34 families with hereditary pancreatitis (167800) but no known missense mutations in PRSS1, PRSS2, SPINK1, or CFTR, Le Marechal et al. (2006) identified triplication of the PRSS1 gene. Some unaffected members of the family were heterozygous for the same triplication, indicating a high but incomplete penetrance of the hereditary pancreatitis caused by the triplication. </p><p>Chauvin et al. (2009) characterized the triplication copy number mutation in the PRSS1 gene and found it to be part of a complex rearrangement that also contains a triplicated 137-kb segment and 21-bp sequence tract. The triplication allele constitutes a gain of 2 tandemly arranged composite duplication blocks, each comprising a copy of the 605-kb segment, a copy of the inverted 137-kb segment, and a copy of the inverted 21-bp sequence tract. All triplications and duplications identified were found to arise from a common founder chromosome. The authors proposed a 2-step process for the generation of the triplication copy number mutation. Chauvin et al. (2009) hypothesized that many human germline copy number variants may arise through replication-based mechanisms during the premeiotic mitotic divisions of germ cells. The low copy repeats generated could then serve to promote nonallelic homologous recombination (NAHR) during meiosis, giving rise to amplified DNA sequences, which could themselves predispose to further recombination events during both mitosis and meiosis. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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PRSS1, ALA121THR
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<br />
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SNP: rs199422123,
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gnomAD: rs199422123,
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ClinVar: RCV000012660, RCV001753414, RCV003234902
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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>This variant, formerly titled HEREDITARY PANCREATITIS, has been reclassified based on the findings of Szmola and Sahin-Toth (2010). </p><p>In affected members of a family with hereditary pancreatitis (167800), Felderbauer et al. (2008) identified a heterozygous G-to-A transition in exon 3 of the PRSS1 gene, resulting in an ala121-to-thr (A121T) substitution. The proband had relatively late disease onset in his thirties, and family history indicated reduced penetrance. In vitro functional expression studies showed that the mutant protein resulted in increased digestion by trypsin (more than 80% compared to wildtype PRSS1) that was calcium-dependent. The findings were consistent with a increased autodegradation and a loss of function mechanism, which was opposite to that observed with the common R122H mutation (276000.0001). </p><p>Szmola and Sahin-Toth (2010) presented evidence that the A121T variant is functionally innocuous and not a cause of pancreatitis. The authors noted that only the index patient in the report of Felderbauer et al. (2008) carried the A121T variant and suffered from chronic pancreatitis. The patient's brother and first cousin, who both carried the variant, had cholelithiasis, and his niece and her mother were asymptomatic carriers. Functional expression studies by Szmola and Sahin-Toth (2010) indicated that autoactivation of trypsinogens by the A121T variant was similar to wildtype with equal enzyme kinetics. Szmola and Sahin-Toth (2010) suggested that the variant may have been assigned clinical relevance based on a perceived analogy with the neighboring disease-causing R122H mutations (276000.0001 and 276000.0008). </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>.0012 PANCREATITIS, HEREDITARY</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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PRSS1, ARG116CYS
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<br />
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SNP: rs387906698,
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gnomAD: rs387906698,
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ClinVar: RCV000022814, RCV004557257
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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>Teich et al. (2006) reported that the 346C-T transition in exon 3 of the PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been identified by 4 independent groups in Turkish, German, and Thai families with hereditary pancreatitis (167800) and in 2 unrelated French patients with pancreatitis. </p><p>In an 11-year-old German girl with hereditary pancreatitis, originally reported by Teich et al. (2002), Kereszturi et al. (2009) showed that trypsinogen misfolding is the likely disease mechanism. The R116C substitution occurs in a surface loop that is highly sensitive to autolytic cleavage. In vitro functional expression studies showed that the R116C mutation resulted in misfolding of the protein, but residual amounts of properly folded protein showed normal activation, catalytic properties, and degradation. Expression of the mutant protein in HEK 293T cells showed decreased secretion compared to wildtype, suggesting that the unpaired cysteine residue at codon 116 interferes with proper protein folding, resulting in the mutant protein being retained inside the cell. Biochemical evidence indicated activation of the unfolded protein response, although there was no evidence of increased caspase-3 (CASP3; 600636) activity. The R116C mutation was also found in the girl's 57-year-old affected maternal grandfather and her 38-year-old unaffected mother, indicating incomplete penetrance. </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>REFERENCES</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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<ol>
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<li>
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Europ. J. Hum. Genet. 10: 100-106, 2002.
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Chauvin, A., Chen, J.-M., Quemener, S., Masson, E., Kehrer-Sawatzki, H., Ohmle, B., Cooper, D. N., Le Marechal, C., Ferec, C.
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Chen, J.-M., Ferec, C.
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Sahin-Toth, M., Graf, L., Toth, M.
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<p class="mim-text-font">
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Sahin-Toth, M., Toth, M.
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<strong>Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen.</strong>
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Biochem. Biophys. Res. Commun. 278: 286-289, 2000.
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[PubMed: 11097832]
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<p class="mim-text-font">
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Sahin-Toth, M.
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Endocr. Metab. Clin. North Am. 35: 303-312, 2006.
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[PubMed: 16632094]
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Tani, T., Kawashima, I., Mita, K., Takiguchi, Y.
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Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M.
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Teich, N., Nemoda, Z., Kohler, H., Heinritz, W., Mossner, J., Keim, V., Sahin-Toth, M.
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Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K., Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C., Ehrlich, G. D.
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Bao Lige - updated : 01/14/2021<br>Cassandra L. Kniffin - updated : 1/19/2011<br>George E. Tiller - updated : 7/8/2010<br>Cassandra L. Kniffin - updated : 6/3/2010<br>Cassandra L. Kniffin - updated : 2/9/2009<br>Cassandra L. Kniffin - updated : 9/18/2008<br>Marla J. F. O'Neill - updated : 3/1/2007<br>Victor A. McKusick - updated : 1/5/2007<br>Victor A. McKusick - updated : 8/24/2006<br>Victor A. McKusick - updated : 4/28/2005<br>Victor A. McKusick - updated : 2/3/2004<br>Victor A. McKusick - updated : 12/27/2002<br>Michael B. Petersen - updated : 10/8/2002<br>Victor A. McKusick - updated : 10/12/2001<br>Victor A. McKusick - updated : 3/27/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Michael J. Wright - updated : 11/3/1999<br>Victor A. McKusick - updated : 1/20/1998
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Victor A. McKusick : 6/4/1986
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