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Entry
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- *608441 - SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1; SYNE1
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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">*608441</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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608441">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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</ul>
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000131018;t=ENST00000367255" 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=23345" 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=608441" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span 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=ENSG00000131018;t=ENST00000367255" 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_001347701,NM_001347702,NM_033071,NM_182961,XM_006715407,XM_006715408,XM_006715409,XM_006715410,XM_006715411,XM_006715412,XM_006715413,XM_006715414,XM_006715415,XM_006715416,XM_006715417,XM_006715420,XM_006715421,XM_006715422,XM_006715423,XM_006715424,XM_006715425,XM_011535641,XM_011535642,XM_011535643,XM_011535644,XM_011535645,XM_017010608,XM_017010609,XM_017010610,XM_017010611,XM_017010612,XM_017010613,XM_017010614,XM_017010615,XM_017010616,XM_017010617,XM_017010618,XM_017010619,XM_047418501,XM_047418502,XM_047418503,XM_047418504,XM_047418505,XM_047418506,XM_047418507,XM_047418508,XM_047418509,XM_047418510,XM_047418511,XM_047418512,XM_047418513" 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_182961" 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=608441" 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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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div><a href="https://hprd.org/summary?hprd_id=09762&isoform_id=09762_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/SYNE1" 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/6330957,12698057,16551439,17227154,17861378,17861386,20521662,21753085,22597198,24417709,28192522,28192628,28195677,28195689,31873576,31873814,34849883,52545673,57999530,60688553,73909082,119568112,119568113,119568114,119568115,119568116,119568117,119568118,119568119,119568120,119568121,119568122,119568123,119568124,152012550,193783098,193784126,194388378,218766404,221045590,330688408,394999650,394999652,394999654,394999656,394999658,394999660,394999662,425906075,578812568,578812570,578812572,578812574,578812576,578812578,578812580,578812582,578812584,578812586,578812588,578812594,578812596,578812598,578812600,578812602,578812604,767942383,767942385,767942387,767942389,767942391,973447311,973447313,1034649436,1034649438,1034649443,1034649447,1034649450,1034649453,1034649458,1034649462,1034649465,1034649468,1034649470,1034649472,1112917086,1112917088,1206484194,1847688288,2217360600,2217360606,2217360609,2217360614,2217360616,2217360623,2217360630,2217360632,2217360634,2217360636,2217360638,2217360647,2217360652,2462607310,2462607312,2462607314,2462607316,2462607318,2462607320,2462607322,2462607324,2462607326,2462607328,2462607330,2462607332,2462607334,2462607336,2462607338,2462607340,2462607342,2462607344,2462607346,2462607348,2462607350,2462607352,2462607354,2462607356,2462607358,2462607360,2462607362,2462607364,2462607366,2462607368,2462607370,2462607372,2462607374,2462607376,2462607378,2462607381,2462607383,2462607385,2462607387,2462607389,2462607391,2462607393,2462607395,2462607397,2462607399,2462607401" 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/Q8NF91" 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 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=23345" 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=ENSG00000131018;t=ENST00000367255" 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=SYNE1" 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=SYNE1" 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+23345" 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/SYNE1" 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:23345" 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/23345" 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=chr6&hgg_gene=ENST00000367255.10&hgg_start=152121687&hgg_end=152637362&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://medlineplus.gov/genetics/gene/syne1" 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=608441[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=608441[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://www.deciphergenomics.org/gene/SYNE1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000131018" 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=SYNE1" 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=SYNE1" 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=SYNE1" 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.LOVD.nl/SYNE1" 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=SYNE1&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/PA134975331" 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:17089" 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/FBgn0261836.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1927152" 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/SYNE1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1927152" 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/23345/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=23345" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000140;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-4172" 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:23345" 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=SYNE1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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608441
|
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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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SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1; SYNE1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
SYNAPTIC NUCLEAR ENVELOPE PROTEIN 1<br />
|
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NUCLEAR ENVELOPE SPECTRIN REPEAT PROTEIN 1<br />
|
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NESPRIN 1<br />
|
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KIAA0796<br />
|
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KIAA1756<br />
|
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KIAA1262
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
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CPG2 ISOFORM, INCLUDED; CPG2, INCLUDED
|
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</span>
|
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</div>
|
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<div>
|
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<span class="h4 mim-font">
|
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|
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CPG2B ISOFORM, INCLUDED; CPG2B, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SYNE1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SYNE1</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/6/963?start=-3&limit=10&highlight=963">6q25.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:152121687-152637362&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'})">6:152,121,687-152,637,362</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>
|
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<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
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<p>The SYNE1 gene encodes nesprin-1, a member of the spectrin family of structural proteins that link the nuclear plasma membrane to the actin cytoskeleton (summary by <a href="#13" class="mim-tip-reference" title="Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others. <strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong> J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24123876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24123876</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24123876">Schuurs-Hoeijmakers et al., 2013</a>). The full-length protein is very large (1 MDa) and contains 8,797 amino acids; SYNE1 encodes multiple isoforms that show differential tissue expression (summary by <a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24123876+27782104" 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="#1" class="mim-tip-reference" title="Apel, E. D., Lewis, R. M., Grady, R. M., Sanes, J. R. <strong>Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction.</strong> J. Biol. Chem. 275: 31986-31995, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10878022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10878022</a>] [<a href="https://doi.org/10.1074/jbc.M004775200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10878022">Apel et al. (2000)</a> isolated a cDNA encoding Syne1 by yeast 2-hybrid analysis of an embryonic mouse cDNA library using mouse Musk (<a href="/entry/601296">601296</a>) as bait. By screening additional mouse cDNA libraries, they identified cDNAs encoding at least 3 Syne1 variants. Syne1 contains multiple spectrin repeats and a 60-amino acid C-terminal region homologous to the Drosophila protein Klarsicht. By database analysis, <a href="#1" class="mim-tip-reference" title="Apel, E. D., Lewis, R. M., Grady, R. M., Sanes, J. R. <strong>Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction.</strong> J. Biol. Chem. 275: 31986-31995, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10878022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10878022</a>] [<a href="https://doi.org/10.1074/jbc.M004775200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10878022">Apel et al. (2000)</a> identified KIAA0796 (<a href="#10" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 5: 277-286, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9872452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9872452</a>] [<a href="https://doi.org/10.1093/dnares/5.5.277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9872452">Nagase et al., 1998</a>) as a partial human ortholog of Syne1. Northern blot analysis of mouse and human tissues detected a 4.7-kb SYNE1A transcript in skeletal and cardiac muscle and a 10-kb SYNE1B transcript in multiple tissues, including heart, muscle, kidney, liver, and brain. RT-PCR analysis showed moderate to high expression of both transcripts in most human tissues examined. Immunofluorescence on adult mouse tissues localized Syne1 to nuclei in skeletal, smooth, and cardiac muscle cells. In skeletal muscle, high levels of expression were detected in nuclei associated with synaptic sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10878022+9872452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M. <strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong> J. Cell Sci. 114: 4485-4498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792814</a>] [<a href="https://doi.org/10.1242/jcs.114.24.4485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792814">Zhang et al. (2001)</a> obtained a rat Syne1 cDNA that was upregulated in differentiated aortic vascular smooth muscle cells. By searching sequence databases using rat Syne1 as probe, followed by PCR and RACE of human spleen and heart cDNA libraries, <a href="#19" class="mim-tip-reference" title="Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M. <strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong> J. Cell Sci. 114: 4485-4498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792814</a>] [<a href="https://doi.org/10.1242/jcs.114.24.4485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792814">Zhang et al. (2001)</a> isolated human cDNAs encoding 2 SYNE1 proteins, which they called nesprin-1-alpha and nesprin-1-beta. Nesprin-1-alpha contains 982 amino acids and nesprin-1-beta contains 3,221 amino acids. They also identified a rare splice variant of nesprin-1-alpha, nesprin-1-alpha-2, that contains an additional 31 amino acids at its N terminus. Both nesprin-1 proteins contain multiple spectrin repeats, a bipartite nuclear localization signal, a transmembrane domain within the C-terminal Klarsicht homology (KASH) region, and several N-glycosylation and phosphorylation sites. Nesprin-1-beta also contains a protein-DNA binding motif. Northern blot analysis detected ubiquitous expression of 3.8- and 10.7-kb transcripts, with highest levels in spleen, peripheral blood leukocytes, and heart. Immunogold and immunofluorescence analyses localized nesprin-1 primarily to the nuclear envelope, with occasional nuclear staining showing colocalization with heterochromatin and the nucleolus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomic sequence analysis, RT-PCR, and RACE, <a href="#18" class="mim-tip-reference" title="Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G. <strong>The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.</strong> Genomics 80: 473-481, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408964</a>]" pmid="12408964">Zhang et al. (2002)</a> extended the sequence of SYNE1 and showed that it encodes an 8,797-amino acid protein with an actin-binding region containing 2 tandem calponin (see <a href="/entry/600806">600806</a>) homology domains at its N terminus. They also identified SYNE1 homologs in Drosophila and C. elegans. <a href="#18" class="mim-tip-reference" title="Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G. <strong>The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.</strong> Genomics 80: 473-481, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408964</a>]" pmid="12408964">Zhang et al. (2002)</a> generated antibody to the newly identified N-terminal portion of SYNE1 and showed that SYNE1 localized to the sarcomeres of cardiac and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cottrell, J. R., Borok, E., Horvath, T. L., Nedivi, E. <strong>CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamine receptors.</strong> Neuron 44: 677-690, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541315</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15541315[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541315">Cottrell et al. (2004)</a> identified 2 brain-specific splice variants of rat Syne1, which they called Cpg2 and Cpg2b, that encode proteins of 941 and 965 amino acids, respectively. The 3-prime UTR of Cpg2 contains an unspliced intron between exons 33 and 34 of the Syne1 gene, and exon 34 is followed by a noncanonical polyadenylation hexamer that is conserved in rats and humans. Compared with Cpg2, Cpg2b has an additional exon at its 5-prime end. RT-PCR detected the 2 Cpg2 transcripts only in rat brain. Immunohistochemical analysis localized Cpg2 to the postsynaptic side of excitatory synapses on rat glutamatergic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database and RACE analyses, followed by PCR and DNA sequencing, <a href="#12" class="mim-tip-reference" title="Rajgor, D., Mellad, J. A., Autore, F., Zhang, Q., Shanahan, C. M. <strong>Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds.</strong> PLoS One 7: e40098, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768332</a>] [<a href="https://doi.org/10.1371/journal.pone.0040098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768332">Rajgor et al. (2012)</a> identified multiple nesprin-1 and nesprin-2 (SYNE2; <a href="/entry/608442">608442</a>) variants. Both nesprin-1 and nesprin-2 underwent alternative splicing and expressed multiple tissue-specific variants generated by alternate initiation and termination. Expression analysis in human fibroblasts and U2OS cells showed that subcellular localization of these variants depended on cell type. Nesprin transcription appeared to be highly adaptable, with a feedback loop regulating variant expression, as perturbing expression of 1 transcript influenced expression of other downstream transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22768332" 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 fusion proteins, <a href="#19" class="mim-tip-reference" title="Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M. <strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong> J. Cell Sci. 114: 4485-4498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792814</a>] [<a href="https://doi.org/10.1242/jcs.114.24.4485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792814">Zhang et al. (2001)</a> determined that SYNE1 requires its C-terminal transmembrane domain to localize to the nuclear envelope. When the transmembrane domain was deleted, the remaining C-terminal domain directed nuclear targeting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cottrell, J. R., Borok, E., Horvath, T. L., Nedivi, E. <strong>CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamine receptors.</strong> Neuron 44: 677-690, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541315</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15541315[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541315">Cottrell et al. (2004)</a> found that RNA interference-mediated knockdown of Cpg2 in cultured rat hippocampal neurons increased the number of postsynaptic clathrin-coated vesicles, some of which trafficked NMDA-type glutamate receptors (see GRIN1; <a href="/entry/138249">138249</a>), disrupted constitutive internalization of glutamate receptors, and inhibited activity-induced internalization of synaptic AMPA-type glutamate receptors (see GRIA1; <a href="/entry/138247">138247</a>). Manipulating Cpg2 levels also affected dendritic spine size. <a href="#4" class="mim-tip-reference" title="Cottrell, J. R., Borok, E., Horvath, T. L., Nedivi, E. <strong>CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamine receptors.</strong> Neuron 44: 677-690, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541315</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15541315[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541315">Cottrell et al. (2004)</a> concluded that CPG2 is a component of a specialized postsynaptic endocytic mechanism devoted to internalization of synaptic proteins, including glutamate receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541315" 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="#11" class="mim-tip-reference" title="Puckelwartz, M. J., Kessler, E., Zhang, Y., Hodzic, D., Randles, K. N., Morris, G., Earley, J. U., Hadhazy, M., Holaska, J. M., Mewborn, S. K., Pytel, P., McNally, E. M. <strong>Disruption of nesprin-1 produces an Emery-Dreifuss muscular dystrophy-like phenotype in mice.</strong> Hum. Molec. Genet. 18: 607-620, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19008300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19008300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19008300[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/10.1093/hmg/ddn386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19008300">Puckelwartz et al. (2009)</a> noted that nesprins, including nesprin-1, participate in a complex that links the nucleoskeleton to the cytoskeleton (LINC). Longer nesprin isoforms with actin-binding domains reside in the outer nuclear membrane, while short nesprin isoforms are tethered to the inner nuclear membrane. The transmembrane KASH domain is required for tethering to the nuclear membrane, and the luminal portion of the KASH domain binds to SUN1 (<a href="/entry/607723">607723</a>) and SUN2 (<a href="/entry/613569">613569</a>). Both SUN proteins and nesprin can interact with lamins (LMNA; <a href="/entry/150330">150330</a>) at the inner nuclear membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19008300" 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="Gob, E., Schmitt, J., Benavente, R., Alsheimer, M. <strong>Mammalian sperm head formation involves different polarization of two novel LINC complexes.</strong> PLoS One 5: e12072, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20711465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20711465</a>] [<a href="https://doi.org/10.1371/journal.pone.0012072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20711465">Gob et al. (2010)</a> found that formation of mouse sperm head involved assembly and different polarization of 2 spermiogenesis-specific LINC complexes. One LINC complex formed through interaction of Sun3 (<a href="/entry/618984">618984</a>) and nesprin-1 and polarized to the posterior pole of the spermatid nuclear envelope. The other LINC complex was nonnuclear and formed through interaction of the eta isoform of Sun1 and nesprin-3 (SYNE3; <a href="/entry/610861">610861</a>) and localized to the anterior pole of the spermatid nucleus. The authors proposed that the 2 LINC complexes connect the differentiating spermatid nucleus to surrounding cytoskeletal structures to enable its well-directed shaping and elongation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20711465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al. (2017)</a> noted that nesprin-1-alpha-2 (120 kD) represents a C-terminal predominantly muscle-specific isoform that contains a KASH domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27782104" 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="#18" class="mim-tip-reference" title="Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G. <strong>The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.</strong> Genomics 80: 473-481, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408964</a>]" pmid="12408964">Zhang et al. (2002)</a> determined that the SYNE1 gene contains 147 exons and spans 550 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408964" 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 FISH, <a href="#19" class="mim-tip-reference" title="Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M. <strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong> J. Cell Sci. 114: 4485-4498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792814</a>] [<a href="https://doi.org/10.1242/jcs.114.24.4485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792814">Zhang et al. (2001)</a> mapped the SYNE1 gene to chromosome 6q25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Autosomal Recessive Spinocerebellar Ataxia 8</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> mapped a candidate interval for a pure form of autosomal recessive cerebellar ataxia (SCAR8; <a href="/entry/610743">610743</a>) to chromosome 6q using genomewide linkage analysis. The candidate interval contained only 1 gene, SYNE1, which spans over 0.5 Mb of genomic DNA. Direct sequencing of SYNE1 identified 2 disease-segregating single-nucleotide polymorphisms (SNPs) that were not detected among 380 age- and ethnicity-matched control chromosomes. This observation led <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> to believe that these 2 variants may be causative mutations for ARCA1 (SCAR8). The first mutation affected the invariant A of the AG splice acceptor site at the junction of exon 85 and intron 84 (<a href="#0001">608441.0001</a>), and the second mutation was located in intron 81, 12 bp upstream of exon 82 (<a href="#0002">608441.0002</a>), creating a new AG cryptic splice acceptor site. RT-PCR and sequencing analysis showed that the detected intronic mutations had functional consequences on the proper splicing of the gene and resulted in premature termination of the protein. Based on the haplotype reconstructions of affected individuals from all of the other families, they identified 3 other different disease haplotypes, suggesting that other mutations could be associated with the disease. A second mutational screen by direct sequencing uncovered 3 additional mutations that segregated with their respective haplotypes and were all predicted to lead to premature termination of the protein: R2906X (<a href="#0003">608441.0003</a>), a 5-bp deletion (<a href="#0004">608441.0004</a>), and Q7640X (<a href="#0005">608441.0005</a>). These additional mutations were not detected among the 380 age- and ethnicity-matched control chromosomes. Because they had identified 5 different mutations in a relatively homogeneous population, <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> predicted that mutations in this gene may be responsible for a substantial fraction of all adult-onset autosomal recessive ataxia syndromes with cerebellar atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" 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 Japanese patients with adult-onset SCAR8, <a href="#8" class="mim-tip-reference" title="Izumi, Y., Miyamoto, R., Morino, H., Yoshizawa, A., Nishinaka, K., Udaka, F., Kameyama, M., Maruyama, H., Kawakami, H. <strong>Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease.</strong> Neurology 80: 600-601, 2013. Note: Erratum: Neurology 80: 1267 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23325900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23325900</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182815529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23325900">Izumi et al. (2013)</a> identified different homozygous truncating mutations in the SYNE1 gene (see, e.g., <a href="#0015">608441.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23325900" 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 23 non-French-Canadian probands with SCAR8, <a href="#14" class="mim-tip-reference" title="Synofzik, M., Smets, K., Mallaret, M., Di Bella, D., Gallenmuller, C., Baets, J., Schulze, M., Magri, S., Sarto, E., Mustafa, M., Deconinck, T., Haack, T., and 18 others. <strong>SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.</strong> Brain 139: 1378-1393, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27086870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27086870</a>] [<a href="https://doi.org/10.1093/brain/aww079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27086870">Synofzik et al. (2016)</a> identified 35 different homozygous or compound heterozygous mutations in the SYNE1 gene (see, e.g., <a href="#0016">608441.0016</a>-<a href="#0017">608441.0017</a>). There were 20 nonsense, 7 frameshift, and 7 splice site mutations, and only 1 missense mutation; mutations occurred throughout the gene. Twenty-two of the patients had biallelic truncating alleles, and 1 was compound heterozygous for a missense and a truncating allele. Five probands were from multiplex families, whereas 18 were simplex cases with no family history of the disorder. All mutations were confirmed by Sanger sequencing, and the mutations segregated with the disorder in families from whom DNA was available. Most of the mutations were absent in the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, although a few were observed at low frequencies. The missense variant (F220S) occurred at a highly conserved residue in the actin-binding domain and was absent from public databases. Analysis of patient cells from 1 family with a truncating and a frameshift mutation showed that the mutations resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Muscle biopsy samples from 3 unrelated patients showed severely decreased or absent SYNE1 immunostaining, also consistent with a loss of protein. Functional studies of the variants and additional studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function. The patients were ascertained from a cohort of 434 index patients from 36 different countries with autosomal recessive ataxia compiled from 7 different European ataxia centers. Those with genetically confirmed SCAR8 accounted for almost 5%, indicating that SCAR8 is more common than previously thought. The findings also indicated that the phenotype of SCAR8 more often than not includes additional complicating features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27086870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Arthrogryposis Multiplex Congenita 3, Myogenic Type</em></strong></p><p>
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In 2 sibs, born of consanguineous Palestinian parents, with myogenic type of arthrogryposis multiplex congenita-3 (AMC3; <a href="/entry/618484">618484</a>), <a href="#2" class="mim-tip-reference" title="Attali, R., Warwar, N., Israel, A., Gurt, I., McNally, E., Puckelwartz, M., Glick, B., Nevo, Y., Ben-Neriah, Z., Melki, J. <strong>Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.</strong> Hum. Molec. Genet. 18: 3462-3469, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542096</a>] [<a href="https://doi.org/10.1093/hmg/ddp290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19542096">Attali et al. (2009)</a> identified a homozygous splice site mutation in the SYNE1 gene (<a href="#0011">608441.0011</a>). Patient fibroblasts showed aberrant splicing with retention of intron 136 and premature termination that would delete the C-terminal KASH domain. There was a 25% decrease in mRNA compared to controls, and no detectable nesprin-1 immunolabeling in patient fibroblasts. <a href="#2" class="mim-tip-reference" title="Attali, R., Warwar, N., Israel, A., Gurt, I., McNally, E., Puckelwartz, M., Glick, B., Nevo, Y., Ben-Neriah, Z., Melki, J. <strong>Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.</strong> Hum. Molec. Genet. 18: 3462-3469, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542096</a>] [<a href="https://doi.org/10.1093/hmg/ddp290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19542096">Attali et al. (2009)</a> concluded that the C-terminal KASH domain is critical for muscle development and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19542096" 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 sibs, born of consanguineous parents (family K168) with AMC3, <a href="#9" class="mim-tip-reference" title="Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others. <strong>Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.</strong> Hum. Molec. Genet. 23: 2279-2289, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24319099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24319099</a>] [<a href="https://doi.org/10.1093/hmg/ddt618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24319099">Laquerriere et al. (2014)</a> identified a homozygous nonsense mutation in the SYNE1 gene (R8193X; <a href="#0018">608441.0018</a>). The mutation, which was found by a combination of genetic mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The authors suggested that the disorder was due to skeletal muscle involvement rather than axoglial. The family was ascertained from a cohort of 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic AMC who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24319099" 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 8-year-old boy, born of consanguineous Turkish parents, with AMC3, <a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al. (2017)</a> identified a homozygous truncating mutation (R8746X; <a href="#0018">608441.0018</a>) at the C terminus. The mutation affected both the short muscle-specific KASH-containing isoform nesprin-1-alpha-2 and the CNS-expressed giant isoform. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutant mRNA was expressed at normal levels, suggesting that normal levels of the truncated protein were expressed. <a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al. (2017)</a> suggested that loss of the KASH domain in SYNE1 is sufficient to cause AMC3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27782104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Emery-Dreifuss Muscular Dystrophy 4</em></strong></p><p>
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In 2 unrelated probands with Emery-Dreifuss muscular dystrophy (EDMD4; <a href="/entry/612998">612998</a>), <a href="#17" class="mim-tip-reference" title="Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. <strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong> Hum. Molec. Genet. 16: 2816-2833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>] [<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761684">Zhang et al. (2007)</a> identified 2 different heterozygous mutations in the SYNE1 gene (R257H, <a href="#0008">608441.0008</a> and E646K, <a href="#0010">608441.0010</a>). Patient fibroblasts and muscle cells showed loss of nuclear envelope integrity with mislocalization of LMNA and emerin (EMD; <a href="/entry/300384">300384</a>). Immunofluorescence studies showed loss of SYNE1 expression in the nuclear envelope and mitochondria of patient fibroblasts. These same changes were also observed in fibroblasts from patients with other genetic forms of EDMD, indicating that loss of nesprin is a characteristic of all forms of EDMD. RNA interference of SYNE1 recapitulated the nuclear defects membrane defects and changes in the organization of intranuclear heterochromatin observed in patient cells. Overall, the findings showed the importance of the nesprin/emerin/lamin complex in the maintenance of nuclear stability and suggested that changes in the binding stoichiometry of these proteins is a feature of EDMD. <a href="#17" class="mim-tip-reference" title="Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. <strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong> Hum. Molec. Genet. 16: 2816-2833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>] [<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761684">Zhang et al. (2007)</a> concluded that the disorder is caused in part by uncoupling of the nucleoskeleton and cytoskeleton and postulated a dominant-negative effect of the SYNE1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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See <a href="#0012">608441.0012</a> for discussion of a possible association of intellectual disability with variation in the SYNE1 gene.</p><p>See <a href="#0014">608441.0014</a> for discussion of a possible association of autism with variation in the SYNE1 gene.</p>
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<p><a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al. (2017)</a> noted that the few reported SYNE1 nonsense or splice site mutations identified in patients with AMC3 all terminate in the C-terminal KASH domain and would be expected to affect at least the major muscle-specific nesprin-1-alpha-2 isoform. Thus, loss of this KASH domain is sufficient to cause AMC3. In contrast, almost all the SCAR8 mutations mainly affect the giant isoform and leave nesprin-1-alpha-2 intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27782104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Puckelwartz, M. J., Kessler, E., Zhang, Y., Hodzic, D., Randles, K. N., Morris, G., Earley, J. U., Hadhazy, M., Holaska, J. M., Mewborn, S. K., Pytel, P., McNally, E. M. <strong>Disruption of nesprin-1 produces an Emery-Dreifuss muscular dystrophy-like phenotype in mice.</strong> Hum. Molec. Genet. 18: 607-620, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19008300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19008300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19008300[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/10.1093/hmg/ddn386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19008300">Puckelwartz et al. (2009)</a> generated mice with C-terminal deletion of Syne1, including the KASH domain. Mice homozygous for this mutation died at or near birth from respiratory failure, whereas surviving mice displayed hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology, and cardiac conduction defects developed. The protein components of the LINC complex, including mutant nesprin-1-alpha, lamin A/C, and Sun2 (Unc84b), were localized at the nuclear membrane in mutant mouse skeletal muscle myofibers; however, mutant nesprin-1 interaction with Sun2 was disrupted in primary myoblasts, resulting from loss of the C-terminal KASH domain. The findings demonstrated the role of the LINC complex and nesprin-1 in EDMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19008300" 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="#20" class="mim-tip-reference" title="Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M. <strong>SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.</strong> Neuron 64: 173-187, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19874786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19874786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19874786[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2009.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19874786">Zhang et al. (2009)</a> showed that Sun1 and Sun2 double-knockout (Sun1/2 DKO) mice and Syne1 and Syne2 double-knockout (Syne1/2 DKO) mice had similar defects in brain development. Sun1/2 DKO and Syne1/2 DKO brains were small and showed defective laminary structures in many brain regions. Examination of neocortex revealed failure of radial neuronal migration, but not tangential migration of interneurons, in both Sun1/2 DKO and Syne1/2 DKO mice. Intracellular movement of nuclei is a prerequisite for proper neuron migration and development, and <a href="#20" class="mim-tip-reference" title="Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M. <strong>SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.</strong> Neuron 64: 173-187, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19874786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19874786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19874786[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2009.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19874786">Zhang et al. (2009)</a> found that Sun1 and Sun2 anchored Syne2 to the nuclear envelope, while Syne1 and Syne2 connected the nuclear envelope to the microtubule network, permitting nuclear movement. <a href="#20" class="mim-tip-reference" title="Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M. <strong>SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.</strong> Neuron 64: 173-187, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19874786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19874786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19874786[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2009.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19874786">Zhang et al. (2009)</a> concluded that a complex made up of SUN1, SUN2, SYNE1, and SYNE2 is required for neuronal nuclear movement and for neuronal migration and development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19874786" 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="#16" class="mim-tip-reference" title="Zhang, J., Felder, A., Liu, Y., Guo, L. T., Lange, S., Dalton, N. D., Gu, Y., Peterson, K. L., Mizisin, A. P., Shelton, G. D., Lieber, R. L., Chen, J. <strong>Nesprin 1 is critical for nuclear positioning and anchorage.</strong> Hum. Molec. Genet. 19: 329-341, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864491[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/10.1093/hmg/ddp499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19864491">Zhang et al. (2010)</a> generated a mouse model in which all isoforms of nesprin-1 containing the C-terminal spectrin-repeat region with or without the KASH domain were ablated. Syne1-knockout mice were marked by decreased survival rates, growth retardation and increased variability in body weight. Additionally, nuclear positioning and anchorage were dysfunctional in skeletal muscle from Syne1-knockout mice. Physiologic testing demonstrated no significant reduction in stress production in nesprin-1-deficient skeletal muscle in either neonatal or adult mice, but a significantly lower exercise capacity in knockout mice. Nuclear deformation testing revealed ineffective strain transmission to nuclei in muscle fibers lacking nesprin-1. <a href="#16" class="mim-tip-reference" title="Zhang, J., Felder, A., Liu, Y., Guo, L. T., Lange, S., Dalton, N. D., Gu, Y., Peterson, K. L., Mizisin, A. P., Shelton, G. D., Lieber, R. L., Chen, J. <strong>Nesprin 1 is critical for nuclear positioning and anchorage.</strong> Hum. Molec. Genet. 19: 329-341, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864491[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/10.1093/hmg/ddp499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19864491">Zhang et al. (2010)</a> concluded that nesprin-1 is essential for normal positioning and anchorage of nuclei in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19864491" 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=608441[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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> rs759460806 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759460806;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/rs759460806?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=rs759460806" 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=rs759460806" 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=RCV000002415 OR RCV000826129 OR RCV000993140 OR RCV001265815 OR RCV001383383 OR RCV005036235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002415, RCV000826129, RCV000993140, RCV001265815, RCV001383383, RCV005036235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002415...</a>
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<p>In affected members of French Canadian families, originating from the Beauce and Bas-St-Laurent regions of the province of Quebec, <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> found that adult-onset autosomal recessive cerebellar ataxia (<a href="/entry/610743">610743</a>) was associated with homozygous mutation in the SYNE1 gene that affected the invariant A of the AG splice acceptor site at the junction of exon 85 and intron 84 (310067A-G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" 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>.0002 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
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SYNE1, IVS81AS, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs606231134 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231134;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/rs606231134?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=rs606231134" 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=rs606231134" 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=RCV000002416 OR RCV000423940 OR RCV000763141 OR RCV003330382 OR RCV004734495 OR RCV005031382" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002416, RCV000423940, RCV000763141, RCV003330382, RCV004734495, RCV005031382" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002416...</a>
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<p>In affected individuals with autosomal recessive cerebellar ataxia (<a href="/entry/610743">610743</a>), <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> found that the disorder was associated with homozygous mutation in intron 81 of the SYNE1 gene, 12 bp upstream of exon 82 (306434A-G), creating a new AG cryptic splice acceptor site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" 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="Dupre, N., Gros-Louis, F., Chrestian, N., Verreault, S., Brunet, D., de Verteuil, D., Brais, B., Bouchard, J.-P., Rouleau, G. A. <strong>Clinical and genetic study of autosomal recessive cerebellar ataxia type 1.</strong> Ann. Neurol. 62: 93-98, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503513</a>] [<a href="https://doi.org/10.1002/ana.21143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503513">Dupre et al. (2007)</a> found that the IVS81-2A-G mutation was the most common mutation among 124 French Canadian patients with SCA8, present at a frequency of 50.8%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17503513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
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SYNE1, ARG2906TER
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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> rs119103243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103243;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/rs119103243?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=rs119103243" 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=rs119103243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002417 OR RCV001288046 OR RCV005041971" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002417, RCV001288046, RCV005041971" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002417...</a>
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<p>In affected members of families with the Beauce type of autosomal recessive cerebellar ataxia (<a href="/entry/610743">610743</a>), <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> described a homozygous nonsense mutation in exon 56 of the SYNE1 gene: 247012A-T, arg2906 to stop (R2906X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
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SYNE1, 5-BP DEL, NT334338
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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> rs794727986 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727986;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/rs794727986?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=rs794727986" 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=rs794727986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000180749 OR RCV001266189 OR RCV002271991 OR RCV004537518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180749, RCV001266189, RCV002271991, RCV004537518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180749...</a>
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<p>In French Canadian individuals with autosomal recessive cerebellar ataxia (<a href="/entry/610743">610743</a>), <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> identified a homozygous 5-bp deletion in the SYNE1 gene, 3343338-3343342delATTTG, predicted to result in a premature termination of the protein at position 5880. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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">rs119103244 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103244;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=rs119103244" 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=rs119103244" 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=RCV000002419 OR RCV000725704" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002419, RCV000725704" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002419...</a>
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<p>In a French Canadian family, <a href="#7" class="mim-tip-reference" title="Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A. <strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong> Nature Genet. 39: 80-85, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159980</a>] [<a href="https://doi.org/10.1038/ng1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159980">Gros-Louis et al. (2007)</a> found that adult-onset autosomal recessive cerebellar ataxia (<a href="/entry/610743">610743</a>) was associated with homozygous mutation in the SYNE1 gene, a 426494C-T transition in exon 126, which resulted in premature termination of the protein at gln7640 (Q7640X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159980" 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">rs119103245 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103245;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=rs119103245" 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=rs119103245" 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=RCV000002420" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002420" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002420</a>
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<p><a href="#5" class="mim-tip-reference" title="Dupre, N., Gros-Louis, F., Chrestian, N., Verreault, S., Brunet, D., de Verteuil, D., Brais, B., Bouchard, J.-P., Rouleau, G. A. <strong>Clinical and genetic study of autosomal recessive cerebellar ataxia type 1.</strong> Ann. Neurol. 62: 93-98, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503513</a>] [<a href="https://doi.org/10.1002/ana.21143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503513">Dupre et al. (2007)</a> identified a 409218C-T transition in exon 118 of the SYNE1 gene, resulting in a gln7836-to-ter (Q7386X) substitution, in genomic DNA from a French Canadian patient with SCAR8 (<a href="/entry/610743">610743</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17503513" 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 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
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SYNE1, 2-BP DEL, 281100TG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231135 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231135;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=rs606231135" 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=rs606231135" 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=RCV000002421" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002421" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002421</a>
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<p><a href="#5" class="mim-tip-reference" title="Dupre, N., Gros-Louis, F., Chrestian, N., Verreault, S., Brunet, D., de Verteuil, D., Brais, B., Bouchard, J.-P., Rouleau, G. A. <strong>Clinical and genetic study of autosomal recessive cerebellar ataxia type 1.</strong> Ann. Neurol. 62: 93-98, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503513</a>] [<a href="https://doi.org/10.1002/ana.21143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503513">Dupre et al. (2007)</a> identified a 2-bp deletion (281100delTG) in exon 71 of the SYNE1 gene, resulting in a termination at codon 4077, in genomic DNA from a French Canadian patient with SCAR8 (<a href="/entry/610743">610743</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17503513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<strong>.0008 EMERY-DREIFUSS MUSCULAR DYSTROPHY 4 WITH VARIABLE FEATURES</strong>
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SYNE1, ARG257HIS
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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> rs119103246 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103246;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/rs119103246?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=rs119103246" 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=rs119103246" 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=RCV000002422 OR RCV001851581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002422, RCV001851581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002422...</a>
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<p>In a man (family 1) with Emery-Dreifuss muscular dystrophy (EDMD4; <a href="/entry/612998">612998</a>), <a href="#17" class="mim-tip-reference" title="Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. <strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong> Hum. Molec. Genet. 16: 2816-2833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>] [<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761684">Zhang et al. (2007)</a> identified a heterozygous 966G-A transition in exon 6 of the SYNE1 gene, resulting in an arg257-to-his (R257H) substitution in the second spectrin repeat. He became wheelchair-bound at age 26 years but had no cardiac involvement. The mutation was not found in 384 control alleles. The patient's unaffected mother did not carry the variant; the father was deceased and not studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<strong>.0009 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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SYNE1, VAL572LEU
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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> rs119103247 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103247;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/rs119103247?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=rs119103247" 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=rs119103247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002423 OR RCV002512675" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002423, RCV002512675" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002423...</a>
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<p>This variant, formerly titled EMERY-DREIFUSS MUSCULAR DYSTROPHY 4, has been reclassified because its pathogenicity has not been confirmed.</p><p>In a patient with a severe form of Emery-Dreifuss muscular dystrophy (family 2) (see <a href="/entry/612998">612998</a> and EDMD5, <a href="/entry/612999">612999</a>), <a href="#17" class="mim-tip-reference" title="Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. <strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong> Hum. Molec. Genet. 16: 2816-2833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>] [<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761684">Zhang et al. (2007)</a> identified heterozygosity for variants in 2 different genes: a 1910G-T transversion in exon 12 of the SYNE1 gene, resulting in a val572-to-leu (V572L) substitution, and a T89M mutation in the SYNE2 gene (<a href="/entry/608442#0001">608442.0001</a>). In vitro functional expression studies showed that V572L protein bound more strongly to emerin (EMD; <a href="/entry/300384">300384</a>) than wildtype SYNE1. The variant was not found in 384 control alleles. However, the patient's unaffected father was heterozygous for the V572L substitution and the patient's affected mother carried only the T89M mutation in SYNE2, casting doubt on the pathogenicity of the V572L variant. Moreover, 3 affected members of an unrelated family (family 4) carried only the T89M variant in SYNE2, consistent with EDMD5, suggesting that the T89M variant is pathogenic. The patient from family 2 with both variants had muscular dystrophy combined with severe dilated cardiomyopathy requiring heart transplant at age 26. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 EMERY-DREIFUSS MUSCULAR DYSTROPHY 4 WITH VARIABLE FEATURES</strong>
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SYNE1, GLU646LYS
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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> rs119103248 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103248;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/rs119103248?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=rs119103248" 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=rs119103248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002424 OR RCV000535163 OR RCV000713651 OR RCV000987800 OR RCV001002110 OR RCV001252121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002424, RCV000535163, RCV000713651, RCV000987800, RCV001002110, RCV001252121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002424...</a>
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<p>In a patient (family 3) with Emery-Dreifuss muscular dystrophy-4 (EDMD4; <a href="/entry/612988">612988</a>), <a href="#17" class="mim-tip-reference" title="Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. <strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong> Hum. Molec. Genet. 16: 2816-2833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>] [<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761684">Zhang et al. (2007)</a> identified a heterozygous 2132G-A transition in exon 13 of the SYNE1 gene, resulting in a glu646-to-lys (E646K) substitution in the third spectrin repeat. The mutation was not found in 384 control alleles. The phenotype was mild and characterized by asymptomatic, moderately increased serum creatine kinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE</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">rs1586285494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586285494;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=rs1586285494" 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=rs1586285494" 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=RCV000002425" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002425" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002425</a>
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<p>In 2 members of a consanguineous Palestinian family with myogenic-type arthrogryposis multiplex congenita (AMC3; <a href="/entry/618484">618484</a>), <a href="#2" class="mim-tip-reference" title="Attali, R., Warwar, N., Israel, A., Gurt, I., McNally, E., Puckelwartz, M., Glick, B., Nevo, Y., Ben-Neriah, Z., Melki, J. <strong>Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.</strong> Hum. Molec. Genet. 18: 3462-3469, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542096</a>] [<a href="https://doi.org/10.1093/hmg/ddp290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19542096">Attali et al. (2009)</a> identified homozygosity for an acceptor splice site mutation 2 basepairs 5-prime to exon 137 in the SYNE1 gene (IVS136-2A-G), which was predicted to result in retention of intron 136 in mRNA, generating a premature stop codon and loss of the C-terminal transmembrane KASH domain. (The protein change is His8105ValfsTer8 (<a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al., 2017</a>).) Patient fibroblasts showed aberrant splicing with retention of intron 136 and premature termination that would delete the C-terminal KASH domain. There was a 25% decrease in mRNA compared to controls, and no detectable nesprin-1 immunolabeling in patient fibroblasts. The disorder was characterized by bilateral clubfoot, decreased fetal movements, hypotonia, delayed motor milestones, and progressive motor decline after the first decade. Muscle biopsies in affected individuals revealed variation in size of muscle fibers without necrosis or fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19542096+27782104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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SYNE1, GLN655ARG AND ALA3088THR
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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> rs398123005 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123005;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/rs398123005?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=rs398123005" 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=rs398123005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9397509 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9397509;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/rs9397509?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=rs9397509" 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=rs9397509" 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=RCV000077790 OR RCV000118457 OR RCV000263930 OR RCV000361444 OR RCV000445089 OR RCV000692632 OR RCV001083042 OR RCV001658072 OR RCV004542857" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077790, RCV000118457, RCV000263930, RCV000361444, RCV000445089, RCV000692632, RCV001083042, RCV001658072, RCV004542857" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077790...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.</p><p>In a Sicilian brother and sister, born of unrelated parents, with mild intellectual disability, <a href="#13" class="mim-tip-reference" title="Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others. <strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong> J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24123876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24123876</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24123876">Schuurs-Hoeijmakers et al. (2013)</a> identified 3 heterozygous missense variants in the SYNE1 gene. A c.1964A-G transition, resulting in a gln655-to-arg (Q655R) substitution, and a c.9262G-A transition, resulting in an ala3088-to-thr (A3088T) substitution, occurred on the same allele and were inherited from the unaffected father. The other allele carried a c.11675T-C transition, resulting in a leu3892-to-ser (L3892S; <a href="#0013">608441.0013</a>) substitution, which was inherited from the unaffected mother. The Q655R and L3892S substitutions are located in 2 of the multiple spectrin repeats of SYNE1, and the A3088T substitution is located in close proximity to such a repeat. All 3 mutations occurred at conserved residues. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. Both patients had spastic paraplegia, axonal neuropathy, and leukoencephalopathy; the sister also had a hypoplastic corpus callosum. No functional studies were performed. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24123876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<strong>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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SYNE1, LEU3892SER
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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> rs180727534 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180727534;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/rs180727534?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=rs180727534" 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=rs180727534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000077791 OR RCV000284405 OR RCV000393083 OR RCV000713587 OR RCV000815827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077791, RCV000284405, RCV000393083, RCV000713587, RCV000815827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077791...</a>
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<p>See <a href="#0012">608441.0012</a> and <a href="#13" class="mim-tip-reference" title="Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others. <strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong> J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24123876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24123876</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24123876">Schuurs-Hoeijmakers et al. (2013)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24123876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 VARIANT OF UNKNOWN SIGNIFICANCE</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> rs587777426 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777426;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/rs587777426?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=rs587777426" 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=rs587777426" 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=RCV000122610 OR RCV001854680" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122610, RCV001854680" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122610...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to autism has not been confirmed.</p><p>In 4 children with autism from a consanguineous family, <a href="#15" class="mim-tip-reference" title="Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., and 37 others. <strong>Using whole-exome sequencing to identify inherited causes of autism.</strong> Neuron 77: 259-273, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23352163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23352163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23352163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23352163">Yu et al. (2013)</a> identified homozygosity for a leu3206-to-met (L3206M) missense mutation in the SYNE1 gene. In this family linkage to 2 loci, one on chromosome 6q25 and the other on 7q33, had been established; no protein-altering variants were found in the 7q33 linkage interval. As mutations in SYNE1 cause different phenotypes, <a href="#15" class="mim-tip-reference" title="Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., and 37 others. <strong>Using whole-exome sequencing to identify inherited causes of autism.</strong> Neuron 77: 259-273, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23352163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23352163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23352163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23352163">Yu et al. (2013)</a> concluded that this was likely a hypomorphic allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23352163" 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>.0015 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
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SYNE1, ARG3597TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231292;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=rs606231292" 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=rs606231292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese patient with autosomal recessive spinocerebellar ataxia-8 (SCAR8; <a href="/entry/610743">610743</a>), <a href="#8" class="mim-tip-reference" title="Izumi, Y., Miyamoto, R., Morino, H., Yoshizawa, A., Nishinaka, K., Udaka, F., Kameyama, M., Maruyama, H., Kawakami, H. <strong>Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease.</strong> Neurology 80: 600-601, 2013. Note: Erratum: Neurology 80: 1267 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23325900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23325900</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182815529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23325900">Izumi et al. (2013)</a> identified a homozygous c.10789C-T transition in the SYNE1 gene, resulting in an arg3597-to-ter (R3597X) substitution. The patient had onset of pure cerebellar ataxia at age 36 years; brain imaging showed cerebellar atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23325900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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> rs1269308421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1269308421;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/rs1269308421?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=rs1269308421" 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=rs1269308421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Belgian sibs (family 12) with a complicated form of autosomal recessive spinocerebellar ataxia-8 (SCAR8; <a href="/entry/610743">610743</a>), <a href="#14" class="mim-tip-reference" title="Synofzik, M., Smets, K., Mallaret, M., Di Bella, D., Gallenmuller, C., Baets, J., Schulze, M., Magri, S., Sarto, E., Mustafa, M., Deconinck, T., Haack, T., and 18 others. <strong>SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.</strong> Brain 139: 1378-1393, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27086870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27086870</a>] [<a href="https://doi.org/10.1093/brain/aww079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27086870">Synofzik et al. (2016)</a> identified compound heterozygous nonsense mutations in the SYNE1 gene: a c.21528C-A transversion (c.21528C-A, NM_033071.3), resulting in a tyr7176-to-ter (Y7176X) substitution, and a c.20935C-T transition, resulting in an arg6979-to-ter (R6979X; <a href="#0017">608441.0017</a>) substitution. The mutations, which were found by next-generation sequencing methods and confirmed by Sanger sequencing, were not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27086870" 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> rs763325410 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs763325410;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/rs763325410?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=rs763325410" 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=rs763325410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.20935C-T transition (c.20935C-T, NM_033071.3) in the SYNE1 gene, resulting in an arg6979-to-ter (R6979X) substitution, that was found in compound heterozygous state in 2 sibs with a severe form of autosomal recessive spinocerebellar ataxia-8 (SCAR8; <a href="/entry/610743">610743</a>) by <a href="#14" class="mim-tip-reference" title="Synofzik, M., Smets, K., Mallaret, M., Di Bella, D., Gallenmuller, C., Baets, J., Schulze, M., Magri, S., Sarto, E., Mustafa, M., Deconinck, T., Haack, T., and 18 others. <strong>SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.</strong> Brain 139: 1378-1393, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27086870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27086870</a>] [<a href="https://doi.org/10.1093/brain/aww079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27086870">Synofzik et al. (2016)</a>, see <a href="#0016">608441.0016</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27086870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE</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> rs760715690 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs760715690;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/rs760715690?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=rs760715690" 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=rs760715690" 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=RCV000352027 OR RCV000787308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000352027, RCV000787308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000352027...</a>
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<p>In 2 sibs, born of consanguineous parents (family K168) with myogenic-type arthrogryposis multiplex congenita (AMC3; <a href="/entry/618484">618484</a>), <a href="#9" class="mim-tip-reference" title="Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others. <strong>Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.</strong> Hum. Molec. Genet. 23: 2279-2289, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24319099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24319099</a>] [<a href="https://doi.org/10.1093/hmg/ddt618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24319099">Laquerriere et al. (2014)</a> identified a homozygous c.24577C-T transition (24577C-T, NM_182961) in exon 136 of the SYNE1 gene, resulting in an arg8193-to-ter (R8193X) substitution. The mutation, which was found by a combination of genetic mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the Exome Variant Server or the dbSNP (build 138) databases. The authors suggested that the disorder was due to skeletal muscle involvement rather than axoglial. The family was ascertained from a cohort of 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic AMC who underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24319099" 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> rs746177326 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs746177326;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/rs746177326?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=rs746177326" 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=rs746177326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old boy, born of consanguineous Turkish parents, with myogenic-type arthrogryposis multiplex congenita (AMC3; <a href="/entry/618484">618484</a>), <a href="#3" class="mim-tip-reference" title="Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. <strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 25: 262-266, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27782104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27782104</a>] [<a href="https://doi.org/10.1038/ejhg.2016.144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27782104">Baumann et al. (2017)</a> identified a homozygous c.26236C-T transition (c.26236C-T, NM_182961.3) in the SYNE1 gene, resulting in an arg8746-to-ter (R8746X) substitution at the C terminus. The mutation affected both the short muscle-specific KASH-containing isoform nesprin-1-alpha-2 and the CNS-expressed giant isoform. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the ExAC database (1 in 121,366 alleles). Analysis of patient cells showed that the mutant mRNA was expressed at normal levels, suggesting that normal levels of the truncated protein were expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27782104" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864491[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=19864491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
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[<a href="https://doi.org/10.1093/hmg/ddp499" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
|
|
<a id="Zhang2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M.
|
|
<strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong>
|
|
Hum. Molec. Genet. 16: 2816-2833, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761684</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm238" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G.
|
|
<strong>The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.</strong>
|
|
Genomics 80: 473-481, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408964</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Zhang2001" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M.
|
|
<strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong>
|
|
J. Cell Sci. 114: 4485-4498, 2001.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792814" 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/10.1242/jcs.114.24.4485" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
|
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<a id="Zhang2009" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M.
|
|
<strong>SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.</strong>
|
|
Neuron 64: 173-187, 2009.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19874786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19874786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19874786[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=19874786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1016/j.neuron.2009.08.018" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
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</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Bao Lige - updated : 08/13/2020
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Bao Lige - updated : 07/26/2019<br>Cassandra L. Kniffin - updated : 07/01/2019<br>Cassandra L. Kniffin - updated : 11/3/2014<br>Ada Hamosh - updated : 6/9/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Patricia A. Hartz - updated : 11/8/2011<br>George E. Tiller - updated : 12/29/2010<br>George E. Tiller - updated : 6/16/2010<br>Cassandra L. Kniffin - updated : 9/2/2009<br>George E. Tiller - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Victor A. McKusick - updated : 1/30/2007<br>Patricia A. Hartz - updated : 2/9/2006
|
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</span>
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</div>
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</div>
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</div>
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<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Laura L. Baxter : 2/3/2004
|
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</span>
|
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</div>
|
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</div>
|
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</div>
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<div>
|
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<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
mgross : 08/13/2020
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
mgross : 08/13/2020<br>carol : 07/30/2020<br>carol : 06/16/2020<br>mgross : 07/26/2019<br>carol : 07/12/2019<br>carol : 07/11/2019<br>ckniffin : 07/01/2019<br>carol : 06/25/2019<br>carol : 09/19/2018<br>carol : 11/13/2014<br>mcolton : 11/4/2014<br>ckniffin : 11/3/2014<br>alopez : 6/9/2014<br>carol : 1/7/2014<br>ckniffin : 1/6/2014<br>mgross : 11/20/2013<br>mgross : 11/15/2011<br>terry : 11/8/2011<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>mgross : 9/20/2010<br>carol : 6/16/2010<br>wwang : 9/9/2009<br>ckniffin : 9/2/2009<br>wwang : 8/19/2009<br>terry : 8/10/2009<br>wwang : 1/22/2008<br>ckniffin : 1/7/2008<br>alopez : 2/2/2007<br>alopez : 2/2/2007<br>terry : 1/30/2007<br>terry : 1/30/2007<br>mgross : 3/8/2006<br>terry : 2/9/2006<br>alopez : 5/17/2004<br>tkritzer : 2/23/2004<br>mgross : 2/12/2004<br>mgross : 2/12/2004<br>mgross : 2/4/2004
|
|
</span>
|
|
</div>
|
|
</div>
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</div>
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</div>
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</div>
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</div>
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|
<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 608441
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 1; SYNE1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SYNAPTIC NUCLEAR ENVELOPE PROTEIN 1<br />
|
|
NUCLEAR ENVELOPE SPECTRIN REPEAT PROTEIN 1<br />
|
|
NESPRIN 1<br />
|
|
KIAA0796<br />
|
|
KIAA1756<br />
|
|
KIAA1262
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
CPG2 ISOFORM, INCLUDED; CPG2, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
CPG2B ISOFORM, INCLUDED; CPG2B, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: SYNE1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
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|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 6q25.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 6:152,121,687-152,637,362 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
6q25.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Arthrogryposis multiplex congenita 3, myogenic type
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
618484
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Emery-Dreifuss muscular dystrophy 4, autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
612998
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia, autosomal recessive 8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610743
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The SYNE1 gene encodes nesprin-1, a member of the spectrin family of structural proteins that link the nuclear plasma membrane to the actin cytoskeleton (summary by Schuurs-Hoeijmakers et al., 2013). The full-length protein is very large (1 MDa) and contains 8,797 amino acids; SYNE1 encodes multiple isoforms that show differential tissue expression (summary by Baumann et al., 2017). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Apel et al. (2000) isolated a cDNA encoding Syne1 by yeast 2-hybrid analysis of an embryonic mouse cDNA library using mouse Musk (601296) as bait. By screening additional mouse cDNA libraries, they identified cDNAs encoding at least 3 Syne1 variants. Syne1 contains multiple spectrin repeats and a 60-amino acid C-terminal region homologous to the Drosophila protein Klarsicht. By database analysis, Apel et al. (2000) identified KIAA0796 (Nagase et al., 1998) as a partial human ortholog of Syne1. Northern blot analysis of mouse and human tissues detected a 4.7-kb SYNE1A transcript in skeletal and cardiac muscle and a 10-kb SYNE1B transcript in multiple tissues, including heart, muscle, kidney, liver, and brain. RT-PCR analysis showed moderate to high expression of both transcripts in most human tissues examined. Immunofluorescence on adult mouse tissues localized Syne1 to nuclei in skeletal, smooth, and cardiac muscle cells. In skeletal muscle, high levels of expression were detected in nuclei associated with synaptic sites. </p><p>Zhang et al. (2001) obtained a rat Syne1 cDNA that was upregulated in differentiated aortic vascular smooth muscle cells. By searching sequence databases using rat Syne1 as probe, followed by PCR and RACE of human spleen and heart cDNA libraries, Zhang et al. (2001) isolated human cDNAs encoding 2 SYNE1 proteins, which they called nesprin-1-alpha and nesprin-1-beta. Nesprin-1-alpha contains 982 amino acids and nesprin-1-beta contains 3,221 amino acids. They also identified a rare splice variant of nesprin-1-alpha, nesprin-1-alpha-2, that contains an additional 31 amino acids at its N terminus. Both nesprin-1 proteins contain multiple spectrin repeats, a bipartite nuclear localization signal, a transmembrane domain within the C-terminal Klarsicht homology (KASH) region, and several N-glycosylation and phosphorylation sites. Nesprin-1-beta also contains a protein-DNA binding motif. Northern blot analysis detected ubiquitous expression of 3.8- and 10.7-kb transcripts, with highest levels in spleen, peripheral blood leukocytes, and heart. Immunogold and immunofluorescence analyses localized nesprin-1 primarily to the nuclear envelope, with occasional nuclear staining showing colocalization with heterochromatin and the nucleolus. </p><p>By genomic sequence analysis, RT-PCR, and RACE, Zhang et al. (2002) extended the sequence of SYNE1 and showed that it encodes an 8,797-amino acid protein with an actin-binding region containing 2 tandem calponin (see 600806) homology domains at its N terminus. They also identified SYNE1 homologs in Drosophila and C. elegans. Zhang et al. (2002) generated antibody to the newly identified N-terminal portion of SYNE1 and showed that SYNE1 localized to the sarcomeres of cardiac and skeletal muscle. </p><p>Cottrell et al. (2004) identified 2 brain-specific splice variants of rat Syne1, which they called Cpg2 and Cpg2b, that encode proteins of 941 and 965 amino acids, respectively. The 3-prime UTR of Cpg2 contains an unspliced intron between exons 33 and 34 of the Syne1 gene, and exon 34 is followed by a noncanonical polyadenylation hexamer that is conserved in rats and humans. Compared with Cpg2, Cpg2b has an additional exon at its 5-prime end. RT-PCR detected the 2 Cpg2 transcripts only in rat brain. Immunohistochemical analysis localized Cpg2 to the postsynaptic side of excitatory synapses on rat glutamatergic neurons. </p><p>By database and RACE analyses, followed by PCR and DNA sequencing, Rajgor et al. (2012) identified multiple nesprin-1 and nesprin-2 (SYNE2; 608442) variants. Both nesprin-1 and nesprin-2 underwent alternative splicing and expressed multiple tissue-specific variants generated by alternate initiation and termination. Expression analysis in human fibroblasts and U2OS cells showed that subcellular localization of these variants depended on cell type. Nesprin transcription appeared to be highly adaptable, with a feedback loop regulating variant expression, as perturbing expression of 1 transcript influenced expression of other downstream transcripts. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using fusion proteins, Zhang et al. (2001) determined that SYNE1 requires its C-terminal transmembrane domain to localize to the nuclear envelope. When the transmembrane domain was deleted, the remaining C-terminal domain directed nuclear targeting. </p><p>Cottrell et al. (2004) found that RNA interference-mediated knockdown of Cpg2 in cultured rat hippocampal neurons increased the number of postsynaptic clathrin-coated vesicles, some of which trafficked NMDA-type glutamate receptors (see GRIN1; 138249), disrupted constitutive internalization of glutamate receptors, and inhibited activity-induced internalization of synaptic AMPA-type glutamate receptors (see GRIA1; 138247). Manipulating Cpg2 levels also affected dendritic spine size. Cottrell et al. (2004) concluded that CPG2 is a component of a specialized postsynaptic endocytic mechanism devoted to internalization of synaptic proteins, including glutamate receptors. </p><p>Puckelwartz et al. (2009) noted that nesprins, including nesprin-1, participate in a complex that links the nucleoskeleton to the cytoskeleton (LINC). Longer nesprin isoforms with actin-binding domains reside in the outer nuclear membrane, while short nesprin isoforms are tethered to the inner nuclear membrane. The transmembrane KASH domain is required for tethering to the nuclear membrane, and the luminal portion of the KASH domain binds to SUN1 (607723) and SUN2 (613569). Both SUN proteins and nesprin can interact with lamins (LMNA; 150330) at the inner nuclear membrane. </p><p>Gob et al. (2010) found that formation of mouse sperm head involved assembly and different polarization of 2 spermiogenesis-specific LINC complexes. One LINC complex formed through interaction of Sun3 (618984) and nesprin-1 and polarized to the posterior pole of the spermatid nuclear envelope. The other LINC complex was nonnuclear and formed through interaction of the eta isoform of Sun1 and nesprin-3 (SYNE3; 610861) and localized to the anterior pole of the spermatid nucleus. The authors proposed that the 2 LINC complexes connect the differentiating spermatid nucleus to surrounding cytoskeletal structures to enable its well-directed shaping and elongation. </p><p>Baumann et al. (2017) noted that nesprin-1-alpha-2 (120 kD) represents a C-terminal predominantly muscle-specific isoform that contains a KASH domain. </p>
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</span>
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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>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zhang et al. (2002) determined that the SYNE1 gene contains 147 exons and spans 550 kb. </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>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH, Zhang et al. (2001) mapped the SYNE1 gene to chromosome 6q25. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Recessive Spinocerebellar Ataxia 8</em></strong></p><p>
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Gros-Louis et al. (2007) mapped a candidate interval for a pure form of autosomal recessive cerebellar ataxia (SCAR8; 610743) to chromosome 6q using genomewide linkage analysis. The candidate interval contained only 1 gene, SYNE1, which spans over 0.5 Mb of genomic DNA. Direct sequencing of SYNE1 identified 2 disease-segregating single-nucleotide polymorphisms (SNPs) that were not detected among 380 age- and ethnicity-matched control chromosomes. This observation led Gros-Louis et al. (2007) to believe that these 2 variants may be causative mutations for ARCA1 (SCAR8). The first mutation affected the invariant A of the AG splice acceptor site at the junction of exon 85 and intron 84 (608441.0001), and the second mutation was located in intron 81, 12 bp upstream of exon 82 (608441.0002), creating a new AG cryptic splice acceptor site. RT-PCR and sequencing analysis showed that the detected intronic mutations had functional consequences on the proper splicing of the gene and resulted in premature termination of the protein. Based on the haplotype reconstructions of affected individuals from all of the other families, they identified 3 other different disease haplotypes, suggesting that other mutations could be associated with the disease. A second mutational screen by direct sequencing uncovered 3 additional mutations that segregated with their respective haplotypes and were all predicted to lead to premature termination of the protein: R2906X (608441.0003), a 5-bp deletion (608441.0004), and Q7640X (608441.0005). These additional mutations were not detected among the 380 age- and ethnicity-matched control chromosomes. Because they had identified 5 different mutations in a relatively homogeneous population, Gros-Louis et al. (2007) predicted that mutations in this gene may be responsible for a substantial fraction of all adult-onset autosomal recessive ataxia syndromes with cerebellar atrophy. </p><p>In 2 unrelated Japanese patients with adult-onset SCAR8, Izumi et al. (2013) identified different homozygous truncating mutations in the SYNE1 gene (see, e.g., 608441.0015). </p><p>Among 23 non-French-Canadian probands with SCAR8, Synofzik et al. (2016) identified 35 different homozygous or compound heterozygous mutations in the SYNE1 gene (see, e.g., 608441.0016-608441.0017). There were 20 nonsense, 7 frameshift, and 7 splice site mutations, and only 1 missense mutation; mutations occurred throughout the gene. Twenty-two of the patients had biallelic truncating alleles, and 1 was compound heterozygous for a missense and a truncating allele. Five probands were from multiplex families, whereas 18 were simplex cases with no family history of the disorder. All mutations were confirmed by Sanger sequencing, and the mutations segregated with the disorder in families from whom DNA was available. Most of the mutations were absent in the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, although a few were observed at low frequencies. The missense variant (F220S) occurred at a highly conserved residue in the actin-binding domain and was absent from public databases. Analysis of patient cells from 1 family with a truncating and a frameshift mutation showed that the mutations resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Muscle biopsy samples from 3 unrelated patients showed severely decreased or absent SYNE1 immunostaining, also consistent with a loss of protein. Functional studies of the variants and additional studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function. The patients were ascertained from a cohort of 434 index patients from 36 different countries with autosomal recessive ataxia compiled from 7 different European ataxia centers. Those with genetically confirmed SCAR8 accounted for almost 5%, indicating that SCAR8 is more common than previously thought. The findings also indicated that the phenotype of SCAR8 more often than not includes additional complicating features. </p><p><strong><em>Arthrogryposis Multiplex Congenita 3, Myogenic Type</em></strong></p><p>
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In 2 sibs, born of consanguineous Palestinian parents, with myogenic type of arthrogryposis multiplex congenita-3 (AMC3; 618484), Attali et al. (2009) identified a homozygous splice site mutation in the SYNE1 gene (608441.0011). Patient fibroblasts showed aberrant splicing with retention of intron 136 and premature termination that would delete the C-terminal KASH domain. There was a 25% decrease in mRNA compared to controls, and no detectable nesprin-1 immunolabeling in patient fibroblasts. Attali et al. (2009) concluded that the C-terminal KASH domain is critical for muscle development and maintenance. </p><p>In 2 sibs, born of consanguineous parents (family K168) with AMC3, Laquerriere et al. (2014) identified a homozygous nonsense mutation in the SYNE1 gene (R8193X; 608441.0018). The mutation, which was found by a combination of genetic mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The authors suggested that the disorder was due to skeletal muscle involvement rather than axoglial. The family was ascertained from a cohort of 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic AMC who underwent exome sequencing. </p><p>In an 8-year-old boy, born of consanguineous Turkish parents, with AMC3, Baumann et al. (2017) identified a homozygous truncating mutation (R8746X; 608441.0018) at the C terminus. The mutation affected both the short muscle-specific KASH-containing isoform nesprin-1-alpha-2 and the CNS-expressed giant isoform. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutant mRNA was expressed at normal levels, suggesting that normal levels of the truncated protein were expressed. Baumann et al. (2017) suggested that loss of the KASH domain in SYNE1 is sufficient to cause AMC3. </p><p><strong><em>Emery-Dreifuss Muscular Dystrophy 4</em></strong></p><p>
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In 2 unrelated probands with Emery-Dreifuss muscular dystrophy (EDMD4; 612998), Zhang et al. (2007) identified 2 different heterozygous mutations in the SYNE1 gene (R257H, 608441.0008 and E646K, 608441.0010). Patient fibroblasts and muscle cells showed loss of nuclear envelope integrity with mislocalization of LMNA and emerin (EMD; 300384). Immunofluorescence studies showed loss of SYNE1 expression in the nuclear envelope and mitochondria of patient fibroblasts. These same changes were also observed in fibroblasts from patients with other genetic forms of EDMD, indicating that loss of nesprin is a characteristic of all forms of EDMD. RNA interference of SYNE1 recapitulated the nuclear defects membrane defects and changes in the organization of intranuclear heterochromatin observed in patient cells. Overall, the findings showed the importance of the nesprin/emerin/lamin complex in the maintenance of nuclear stability and suggested that changes in the binding stoichiometry of these proteins is a feature of EDMD. Zhang et al. (2007) concluded that the disorder is caused in part by uncoupling of the nucleoskeleton and cytoskeleton and postulated a dominant-negative effect of the SYNE1 mutations. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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See 608441.0012 for discussion of a possible association of intellectual disability with variation in the SYNE1 gene.</p><p>See 608441.0014 for discussion of a possible association of autism with variation in the SYNE1 gene.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Baumann et al. (2017) noted that the few reported SYNE1 nonsense or splice site mutations identified in patients with AMC3 all terminate in the C-terminal KASH domain and would be expected to affect at least the major muscle-specific nesprin-1-alpha-2 isoform. Thus, loss of this KASH domain is sufficient to cause AMC3. In contrast, almost all the SCAR8 mutations mainly affect the giant isoform and leave nesprin-1-alpha-2 intact. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Puckelwartz et al. (2009) generated mice with C-terminal deletion of Syne1, including the KASH domain. Mice homozygous for this mutation died at or near birth from respiratory failure, whereas surviving mice displayed hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology, and cardiac conduction defects developed. The protein components of the LINC complex, including mutant nesprin-1-alpha, lamin A/C, and Sun2 (Unc84b), were localized at the nuclear membrane in mutant mouse skeletal muscle myofibers; however, mutant nesprin-1 interaction with Sun2 was disrupted in primary myoblasts, resulting from loss of the C-terminal KASH domain. The findings demonstrated the role of the LINC complex and nesprin-1 in EDMD. </p><p>Zhang et al. (2009) showed that Sun1 and Sun2 double-knockout (Sun1/2 DKO) mice and Syne1 and Syne2 double-knockout (Syne1/2 DKO) mice had similar defects in brain development. Sun1/2 DKO and Syne1/2 DKO brains were small and showed defective laminary structures in many brain regions. Examination of neocortex revealed failure of radial neuronal migration, but not tangential migration of interneurons, in both Sun1/2 DKO and Syne1/2 DKO mice. Intracellular movement of nuclei is a prerequisite for proper neuron migration and development, and Zhang et al. (2009) found that Sun1 and Sun2 anchored Syne2 to the nuclear envelope, while Syne1 and Syne2 connected the nuclear envelope to the microtubule network, permitting nuclear movement. Zhang et al. (2009) concluded that a complex made up of SUN1, SUN2, SYNE1, and SYNE2 is required for neuronal nuclear movement and for neuronal migration and development. </p><p>Zhang et al. (2010) generated a mouse model in which all isoforms of nesprin-1 containing the C-terminal spectrin-repeat region with or without the KASH domain were ablated. Syne1-knockout mice were marked by decreased survival rates, growth retardation and increased variability in body weight. Additionally, nuclear positioning and anchorage were dysfunctional in skeletal muscle from Syne1-knockout mice. Physiologic testing demonstrated no significant reduction in stress production in nesprin-1-deficient skeletal muscle in either neonatal or adult mice, but a significantly lower exercise capacity in knockout mice. Nuclear deformation testing revealed ineffective strain transmission to nuclei in muscle fibers lacking nesprin-1. Zhang et al. (2010) concluded that nesprin-1 is essential for normal positioning and anchorage of nuclei in skeletal muscle. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 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 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, IVS84AS, A-G, -2
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<br />
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SNP: rs759460806,
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gnomAD: rs759460806,
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ClinVar: RCV000002415, RCV000826129, RCV000993140, RCV001265815, RCV001383383, RCV005036235
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of French Canadian families, originating from the Beauce and Bas-St-Laurent regions of the province of Quebec, Gros-Louis et al. (2007) found that adult-onset autosomal recessive cerebellar ataxia (610743) was associated with homozygous mutation in the SYNE1 gene that affected the invariant A of the AG splice acceptor site at the junction of exon 85 and intron 84 (310067A-G). </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 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, IVS81AS, A-G, -2
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<br />
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SNP: rs606231134,
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gnomAD: rs606231134,
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ClinVar: RCV000002416, RCV000423940, RCV000763141, RCV003330382, RCV004734495, RCV005031382
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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 individuals with autosomal recessive cerebellar ataxia (610743), Gros-Louis et al. (2007) found that the disorder was associated with homozygous mutation in intron 81 of the SYNE1 gene, 12 bp upstream of exon 82 (306434A-G), creating a new AG cryptic splice acceptor site. </p><p>Dupre et al. (2007) found that the IVS81-2A-G mutation was the most common mutation among 124 French Canadian patients with SCA8, present at a frequency of 50.8%. </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 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, ARG2906TER
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<br />
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SNP: rs119103243,
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gnomAD: rs119103243,
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ClinVar: RCV000002417, RCV001288046, RCV005041971
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of families with the Beauce type of autosomal recessive cerebellar ataxia (610743), Gros-Louis et al. (2007) described a homozygous nonsense mutation in exon 56 of the SYNE1 gene: 247012A-T, arg2906 to stop (R2906X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, 5-BP DEL, NT334338
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<br />
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SNP: rs794727986,
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gnomAD: rs794727986,
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ClinVar: RCV000180749, RCV001266189, RCV002271991, RCV004537518
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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 French Canadian individuals with autosomal recessive cerebellar ataxia (610743), Gros-Louis et al. (2007) identified a homozygous 5-bp deletion in the SYNE1 gene, 3343338-3343342delATTTG, predicted to result in a premature termination of the protein at position 5880. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, GLN7640TER
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<br />
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SNP: rs119103244,
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ClinVar: RCV000002419, RCV000725704
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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 French Canadian family, Gros-Louis et al. (2007) found that adult-onset autosomal recessive cerebellar ataxia (610743) was associated with homozygous mutation in the SYNE1 gene, a 426494C-T transition in exon 126, which resulted in premature termination of the protein at gln7640 (Q7640X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, GLN7386TER
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<br />
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SNP: rs119103245,
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ClinVar: RCV000002420
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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>Dupre et al. (2007) identified a 409218C-T transition in exon 118 of the SYNE1 gene, resulting in a gln7836-to-ter (Q7386X) substitution, in genomic DNA from a French Canadian patient with SCAR8 (610743). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</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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SYNE1, 2-BP DEL, 281100TG
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<br />
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SNP: rs606231135,
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ClinVar: RCV000002421
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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>Dupre et al. (2007) identified a 2-bp deletion (281100delTG) in exon 71 of the SYNE1 gene, resulting in a termination at codon 4077, in genomic DNA from a French Canadian patient with SCAR8 (610743). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 EMERY-DREIFUSS MUSCULAR DYSTROPHY 4 WITH VARIABLE FEATURES</strong>
|
|
</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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SYNE1, ARG257HIS
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<br />
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SNP: rs119103246,
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gnomAD: rs119103246,
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ClinVar: RCV000002422, RCV001851581
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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 man (family 1) with Emery-Dreifuss muscular dystrophy (EDMD4; 612998), Zhang et al. (2007) identified a heterozygous 966G-A transition in exon 6 of the SYNE1 gene, resulting in an arg257-to-his (R257H) substitution in the second spectrin repeat. He became wheelchair-bound at age 26 years but had no cardiac involvement. The mutation was not found in 384 control alleles. The patient's unaffected mother did not carry the variant; the father was deceased and not studied. </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>.0009 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
SYNE1, VAL572LEU
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<br />
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SNP: rs119103247,
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|
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gnomAD: rs119103247,
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ClinVar: RCV000002423, RCV002512675
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled EMERY-DREIFUSS MUSCULAR DYSTROPHY 4, has been reclassified because its pathogenicity has not been confirmed.</p><p>In a patient with a severe form of Emery-Dreifuss muscular dystrophy (family 2) (see 612998 and EDMD5, 612999), Zhang et al. (2007) identified heterozygosity for variants in 2 different genes: a 1910G-T transversion in exon 12 of the SYNE1 gene, resulting in a val572-to-leu (V572L) substitution, and a T89M mutation in the SYNE2 gene (608442.0001). In vitro functional expression studies showed that V572L protein bound more strongly to emerin (EMD; 300384) than wildtype SYNE1. The variant was not found in 384 control alleles. However, the patient's unaffected father was heterozygous for the V572L substitution and the patient's affected mother carried only the T89M mutation in SYNE2, casting doubt on the pathogenicity of the V572L variant. Moreover, 3 affected members of an unrelated family (family 4) carried only the T89M variant in SYNE2, consistent with EDMD5, suggesting that the T89M variant is pathogenic. The patient from family 2 with both variants had muscular dystrophy combined with severe dilated cardiomyopathy requiring heart transplant at age 26. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 EMERY-DREIFUSS MUSCULAR DYSTROPHY 4 WITH VARIABLE FEATURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
SYNE1, GLU646LYS
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|
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|
|
<br />
|
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|
|
SNP: rs119103248,
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|
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|
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gnomAD: rs119103248,
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|
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|
|
|
ClinVar: RCV000002424, RCV000535163, RCV000713651, RCV000987800, RCV001002110, RCV001252121
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (family 3) with Emery-Dreifuss muscular dystrophy-4 (EDMD4; 612988), Zhang et al. (2007) identified a heterozygous 2132G-A transition in exon 13 of the SYNE1 gene, resulting in a glu646-to-lys (E646K) substitution in the third spectrin repeat. The mutation was not found in 384 control alleles. The phenotype was mild and characterized by asymptomatic, moderately increased serum creatine kinase. </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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
SYNE1, IVS136AS, A-G, -2
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs1586285494,
|
|
|
|
|
|
|
|
ClinVar: RCV000002425
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 members of a consanguineous Palestinian family with myogenic-type arthrogryposis multiplex congenita (AMC3; 618484), Attali et al. (2009) identified homozygosity for an acceptor splice site mutation 2 basepairs 5-prime to exon 137 in the SYNE1 gene (IVS136-2A-G), which was predicted to result in retention of intron 136 in mRNA, generating a premature stop codon and loss of the C-terminal transmembrane KASH domain. (The protein change is His8105ValfsTer8 (Baumann et al., 2017).) Patient fibroblasts showed aberrant splicing with retention of intron 136 and premature termination that would delete the C-terminal KASH domain. There was a 25% decrease in mRNA compared to controls, and no detectable nesprin-1 immunolabeling in patient fibroblasts. The disorder was characterized by bilateral clubfoot, decreased fetal movements, hypotonia, delayed motor milestones, and progressive motor decline after the first decade. Muscle biopsies in affected individuals revealed variation in size of muscle fibers without necrosis or fibrosis. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SYNE1, GLN655ARG AND ALA3088THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398123005, rs9397509,
|
|
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|
|
|
gnomAD: rs398123005, rs9397509,
|
|
|
|
|
|
ClinVar: RCV000077790, RCV000118457, RCV000263930, RCV000361444, RCV000445089, RCV000692632, RCV001083042, RCV001658072, RCV004542857
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.</p><p>In a Sicilian brother and sister, born of unrelated parents, with mild intellectual disability, Schuurs-Hoeijmakers et al. (2013) identified 3 heterozygous missense variants in the SYNE1 gene. A c.1964A-G transition, resulting in a gln655-to-arg (Q655R) substitution, and a c.9262G-A transition, resulting in an ala3088-to-thr (A3088T) substitution, occurred on the same allele and were inherited from the unaffected father. The other allele carried a c.11675T-C transition, resulting in a leu3892-to-ser (L3892S; 608441.0013) substitution, which was inherited from the unaffected mother. The Q655R and L3892S substitutions are located in 2 of the multiple spectrin repeats of SYNE1, and the A3088T substitution is located in close proximity to such a repeat. All 3 mutations occurred at conserved residues. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. Both patients had spastic paraplegia, axonal neuropathy, and leukoencephalopathy; the sister also had a hypoplastic corpus callosum. No functional studies were performed. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SYNE1, LEU3892SER
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs180727534,
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|
|
|
|
|
gnomAD: rs180727534,
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|
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|
|
|
ClinVar: RCV000077791, RCV000284405, RCV000393083, RCV000713587, RCV000815827
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 608441.0012 and Schuurs-Hoeijmakers et al. (2013). </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>.0014 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SYNE1, LEU3206MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777426,
|
|
|
|
|
|
gnomAD: rs587777426,
|
|
|
|
|
|
ClinVar: RCV000122610, RCV001854680
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to autism has not been confirmed.</p><p>In 4 children with autism from a consanguineous family, Yu et al. (2013) identified homozygosity for a leu3206-to-met (L3206M) missense mutation in the SYNE1 gene. In this family linkage to 2 loci, one on chromosome 6q25 and the other on 7q33, had been established; no protein-altering variants were found in the 7q33 linkage interval. As mutations in SYNE1 cause different phenotypes, Yu et al. (2013) concluded that this was likely a hypomorphic allele. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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|
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SYNE1, ARG3597TER
|
|
|
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|
|
<br />
|
|
|
|
SNP: rs606231292,
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ClinVar: RCV000144953
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|
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</span>
|
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</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with autosomal recessive spinocerebellar ataxia-8 (SCAR8; 610743), Izumi et al. (2013) identified a homozygous c.10789C-T transition in the SYNE1 gene, resulting in an arg3597-to-ter (R3597X) substitution. The patient had onset of pure cerebellar ataxia at age 36 years; brain imaging showed cerebellar atrophy. </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>.0016 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SYNE1, TYR7176TER
|
|
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<br />
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SNP: rs1269308421,
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|
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gnomAD: rs1269308421,
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ClinVar: RCV000787306
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|
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Belgian sibs (family 12) with a complicated form of autosomal recessive spinocerebellar ataxia-8 (SCAR8; 610743), Synofzik et al. (2016) identified compound heterozygous nonsense mutations in the SYNE1 gene: a c.21528C-A transversion (c.21528C-A, NM_033071.3), resulting in a tyr7176-to-ter (Y7176X) substitution, and a c.20935C-T transition, resulting in an arg6979-to-ter (R6979X; 608441.0017) substitution. The mutations, which were found by next-generation sequencing methods and confirmed by Sanger sequencing, were not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function. </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>
|
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<span class="mim-font">
|
|
<strong>.0017 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
SYNE1, ARG6979TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs763325410,
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|
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gnomAD: rs763325410,
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ClinVar: RCV000519943, RCV000787307, RCV001814183
|
|
|
|
|
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</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the c.20935C-T transition (c.20935C-T, NM_033071.3) in the SYNE1 gene, resulting in an arg6979-to-ter (R6979X) substitution, that was found in compound heterozygous state in 2 sibs with a severe form of autosomal recessive spinocerebellar ataxia-8 (SCAR8; 610743) by Synofzik et al. (2016), see 608441.0016. </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">
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<strong>.0018 ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE</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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SYNE1, ARG8193TER
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<br />
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SNP: rs760715690,
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gnomAD: rs760715690,
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ClinVar: RCV000352027, RCV000787308
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</span>
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<p>In 2 sibs, born of consanguineous parents (family K168) with myogenic-type arthrogryposis multiplex congenita (AMC3; 618484), Laquerriere et al. (2014) identified a homozygous c.24577C-T transition (24577C-T, NM_182961) in exon 136 of the SYNE1 gene, resulting in an arg8193-to-ter (R8193X) substitution. The mutation, which was found by a combination of genetic mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the Exome Variant Server or the dbSNP (build 138) databases. The authors suggested that the disorder was due to skeletal muscle involvement rather than axoglial. The family was ascertained from a cohort of 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic AMC who underwent exome sequencing. </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>.0019 ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE</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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SYNE1, ARG8746TER
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<br />
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SNP: rs746177326,
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gnomAD: rs746177326,
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ClinVar: RCV000787309
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</span>
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<span class="mim-text-font">
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<p>In an 8-year-old boy, born of consanguineous Turkish parents, with myogenic-type arthrogryposis multiplex congenita (AMC3; 618484), Baumann et al. (2017) identified a homozygous c.26236C-T transition (c.26236C-T, NM_182961.3) in the SYNE1 gene, resulting in an arg8746-to-ter (R8746X) substitution at the C terminus. The mutation affected both the short muscle-specific KASH-containing isoform nesprin-1-alpha-2 and the CNS-expressed giant isoform. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the ExAC database (1 in 121,366 alleles). Analysis of patient cells showed that the mutant mRNA was expressed at normal levels, suggesting that normal levels of the truncated protein were expressed. </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>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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<p class="mim-text-font">
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Apel, E. D., Lewis, R. M., Grady, R. M., Sanes, J. R.
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<strong>Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction.</strong>
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[PubMed: 10878022]
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[Full Text: https://doi.org/10.1074/jbc.M004775200]
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</li>
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<li>
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<p class="mim-text-font">
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Attali, R., Warwar, N., Israel, A., Gurt, I., McNally, E., Puckelwartz, M., Glick, B., Nevo, Y., Ben-Neriah, Z., Melki, J.
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<strong>Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.</strong>
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Hum. Molec. Genet. 18: 3462-3469, 2009.
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<li>
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<p class="mim-text-font">
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Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R.
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<strong>Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.</strong>
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Europ. J. Hum. Genet. 25: 262-266, 2017.
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Cottrell, J. R., Borok, E., Horvath, T. L., Nedivi, E.
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<p class="mim-text-font">
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Dupre, N., Gros-Louis, F., Chrestian, N., Verreault, S., Brunet, D., de Verteuil, D., Brais, B., Bouchard, J.-P., Rouleau, G. A.
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<p class="mim-text-font">
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Gob, E., Schmitt, J., Benavente, R., Alsheimer, M.
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<strong>Mammalian sperm head formation involves different polarization of two novel LINC complexes.</strong>
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PLoS One 5: e12072, 2010. Note: Electronic Article.
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[PubMed: 20711465]
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<p class="mim-text-font">
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Gros-Louis, F., Dupre, N., Dion, P., Fox, M. A., Laurent, S., Verreault, S., Sanes, J. R., Bouchard, J.-P., Rouleau, G. A.
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<strong>Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.</strong>
|
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Nature Genet. 39: 80-85, 2007.
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<p class="mim-text-font">
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Izumi, Y., Miyamoto, R., Morino, H., Yoshizawa, A., Nishinaka, K., Udaka, F., Kameyama, M., Maruyama, H., Kawakami, H.
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|
<strong>Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease.</strong>
|
|
Neurology 80: 600-601, 2013. Note: Erratum: Neurology 80: 1267 only, 2013.
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[PubMed: 23325900]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3182815529]
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<p class="mim-text-font">
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Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others.
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<strong>Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.</strong>
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Hum. Molec. Genet. 23: 2279-2289, 2014.
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[PubMed: 24319099]
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[Full Text: https://doi.org/10.1093/hmg/ddt618]
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Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
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DNA Res. 5: 277-286, 1998.
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[Full Text: https://doi.org/10.1093/dnares/5.5.277]
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<p class="mim-text-font">
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Puckelwartz, M. J., Kessler, E., Zhang, Y., Hodzic, D., Randles, K. N., Morris, G., Earley, J. U., Hadhazy, M., Holaska, J. M., Mewborn, S. K., Pytel, P., McNally, E. M.
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<strong>Disruption of nesprin-1 produces an Emery-Dreifuss muscular dystrophy-like phenotype in mice.</strong>
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Hum. Molec. Genet. 18: 607-620, 2009.
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<p class="mim-text-font">
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Rajgor, D., Mellad, J. A., Autore, F., Zhang, Q., Shanahan, C. M.
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<strong>Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds.</strong>
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PLoS One 7: e40098, 2012. Note: Electronic Article.
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Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others.
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<strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong>
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<p class="mim-text-font">
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Synofzik, M., Smets, K., Mallaret, M., Di Bella, D., Gallenmuller, C., Baets, J., Schulze, M., Magri, S., Sarto, E., Mustafa, M., Deconinck, T., Haack, T., and 18 others.
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<strong>SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.</strong>
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Brain 139: 1378-1393, 2016.
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<p class="mim-text-font">
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Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., and 37 others.
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<strong>Using whole-exome sequencing to identify inherited causes of autism.</strong>
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Neuron 77: 259-273, 2013.
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<p class="mim-text-font">
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Zhang, J., Felder, A., Liu, Y., Guo, L. T., Lange, S., Dalton, N. D., Gu, Y., Peterson, K. L., Mizisin, A. P., Shelton, G. D., Lieber, R. L., Chen, J.
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<strong>Nesprin 1 is critical for nuclear positioning and anchorage.</strong>
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Hum. Molec. Genet. 19: 329-341, 2010.
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<p class="mim-text-font">
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Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M.
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<strong>Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.</strong>
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Hum. Molec. Genet. 16: 2816-2833, 2007.
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[PubMed: 17761684]
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<li>
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<p class="mim-text-font">
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Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G.
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<strong>The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.</strong>
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Genomics 80: 473-481, 2002.
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[PubMed: 12408964]
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<li>
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<p class="mim-text-font">
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Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M.
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<strong>Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.</strong>
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J. Cell Sci. 114: 4485-4498, 2001.
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[PubMed: 11792814]
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[Full Text: https://doi.org/10.1242/jcs.114.24.4485]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M.
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<strong>SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.</strong>
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Neuron 64: 173-187, 2009.
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[PubMed: 19874786]
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[Full Text: https://doi.org/10.1016/j.neuron.2009.08.018]
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</li>
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</ol>
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<div>
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</div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/13/2020<br>Bao Lige - updated : 07/26/2019<br>Cassandra L. Kniffin - updated : 07/01/2019<br>Cassandra L. Kniffin - updated : 11/3/2014<br>Ada Hamosh - updated : 6/9/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Patricia A. Hartz - updated : 11/8/2011<br>George E. Tiller - updated : 12/29/2010<br>George E. Tiller - updated : 6/16/2010<br>Cassandra L. Kniffin - updated : 9/2/2009<br>George E. Tiller - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Victor A. McKusick - updated : 1/30/2007<br>Patricia A. Hartz - updated : 2/9/2006
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Laura L. Baxter : 2/3/2004
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Edit History:
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mgross : 08/13/2020<br>mgross : 08/13/2020<br>carol : 07/30/2020<br>carol : 06/16/2020<br>mgross : 07/26/2019<br>carol : 07/12/2019<br>carol : 07/11/2019<br>ckniffin : 07/01/2019<br>carol : 06/25/2019<br>carol : 09/19/2018<br>carol : 11/13/2014<br>mcolton : 11/4/2014<br>ckniffin : 11/3/2014<br>alopez : 6/9/2014<br>carol : 1/7/2014<br>ckniffin : 1/6/2014<br>mgross : 11/20/2013<br>mgross : 11/15/2011<br>terry : 11/8/2011<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>mgross : 9/20/2010<br>carol : 6/16/2010<br>wwang : 9/9/2009<br>ckniffin : 9/2/2009<br>wwang : 8/19/2009<br>terry : 8/10/2009<br>wwang : 1/22/2008<br>ckniffin : 1/7/2008<br>alopez : 2/2/2007<br>alopez : 2/2/2007<br>terry : 1/30/2007<br>terry : 1/30/2007<br>mgross : 3/8/2006<br>terry : 2/9/2006<br>alopez : 5/17/2004<br>tkritzer : 2/23/2004<br>mgross : 2/12/2004<br>mgross : 2/12/2004<br>mgross : 2/4/2004
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