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Entry
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- *602568 - METHIONINE SYNTHASE REDUCTASE; MTRR
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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">*602568</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602568">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000124275;t=ENST00000440940" 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=4552" 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=602568" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000124275;t=ENST00000440940" 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_001364440,NM_001364441,NM_001364442,NM_002454,NM_024010,NR_134480,NR_134481,NR_134482,NR_157168,NR_157169,NR_157170,NR_157171,NR_157172,NR_157173,NR_157174,NR_157175,NR_157176,NR_157177,NR_157178,XM_024446064,XM_047417233,XM_047417234,XM_047417235,XM_047417236,XM_047417237,XM_047417238" 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_002454" 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=602568" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=03979&isoform_id=03979_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/MTRR" 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/2981303,6561339,6572540,6572541,80479050,119628495,119628496,119628497,119628498,127798340,169790958,1370494114,1402531506,1402624270,1402624609,1402625742,1559951228,2120574005,2120574007,2120574009,2120574011,2120574013,2120574015,2120574017,2120574019,2120574021,2120574023,2120574025,2120574027,2120574029,2120574031,2120574033,2120574035,2120574037,2120574039,2120574041,2120574043,2120574045,2120574047,2120574049,2120574051,2120574053,2120574055,2120574057,2120574059,2120574061,2120574063,2120574065,2120574067,2120574069,2120574071,2120574073,2120574075,2120574077,2120574079,2120574081,2120574083,2120574085,2120574087,2120574089,2120574091,2120574093,2120574095,2120574097,2120574099,2120574101,2120574103,2120574105,2120574107,2120574109,2120574111,2120574113,2120574115,2120574117,2120574119,2120574121,2120574123,2120574125,2120574127,2120574129,2120574131,2120574133,2120574135,2120574137,2120574139,2120574141,2120574143,2120574145,2120574147,2120574149,2120574151,2120574153,2120574155,2120574157,2120574159,2120574161,2120574163,2120574165,2120574167,2120574169,2120574171,2120574173,2120574175,2120574177,2120574179,2120574181,2120574183,2120574185,2120574187,2120574189,2120574191,2120574193,2120574195,2120574197,2120574199,2120574201,2120574203,2120574205,2120574207,2120574209,2120574211,2120574213,2120574215,2120574217,2120574219,2120574221,2120574223,2120574225,2120574227,2120574229,2120574231,2120574233,2120574235,2120574237,2120574239,2120574241,2120574243,2120574245,2120574247,2120574249,2120574251,2120574253,2120574255,2120574257,2120574259,2120574261,2120574263,2120574265,2120574267,2120574269,2120574271,2120574273,2120574275,2120574277,2120574279,2120574281,2120574283,2120574285,2120574287,2120574289,2120574291,2120574293,2120574295,2120574297,2120574299,2120574301,2120574303,2120574305,2120574307,2120574309,2120574311,2120574313,2120574315,2120574317,2120574319,2120574321,2120574323,2120574325,2120574327,2120574329,2120574331,2120574333,2120574335,2120574337,2120574339,2120574341,2120574343,2120574345,2120574347,2120574349,2120574351,2120574353,2120574355,2120574357,2120574359,2120574361,2120574363,2120574365,2120574367,2120574369,2120574371,2120574373,2120574375,2120574377,2120574379,2120574381,2120574383,2120574385,2120574387,2120574389,2120574391,2120574393,2120574395,2120574397,2120574399,2120574401,2120574403,2120574405,2120574407,2120574409,2120574411,2120574413,2120574415,2120574417,2120574419,2120574421,2120574423,2120574425,2120574427,2120574429,2120574431,2120574433,2120574435,2120574437,2120574439,2120574441,2120574443,2120574445,2120574447,2120574449,2120574451,2120575589,2120575591,2217355944,2217355946,2217355948,2217355950,2217355952,2217355954,2462602651,2462602654,2462602656,2462602659,2462602661,2462602663,2462602665" 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/Q9UBK8" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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<div 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=4552" 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=ENSG00000124275;t=ENST00000440940" 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=MTRR" 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=MTRR" 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+4552" 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/MTRR" 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:4552" 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/4552" 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=chr5&hgg_gene=ENST00000440940.7&hgg_start=7850859&hgg_end=7901113&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7473" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7473" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/mtrr" 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=602568[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=602568[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/MTRR/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/ENSG00000124275" 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=MTRR" 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=MTRR" 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=MTRR" 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://databases.lovd.nl/genomed/home.php?select_db=MTRR" 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=MTRR&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/PA31277" 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:7473" 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/FBgn0038429.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:1891037" 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/MTRR#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:1891037" 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/4552/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=4552" 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=WBGene00006510;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-101115-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4552" 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=MTRR&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1296847007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602568
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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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METHIONINE SYNTHASE REDUCTASE; MTRR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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MSR
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MTRR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MTRR</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/5/43?start=-3&limit=10&highlight=43">5p15.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:7850859-7901113&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'})">5:7,850,859-7,901,113</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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{Neural tube defects, folate-sensitive, susceptibility to}
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Homocystinuria-megaloblastic anemia, cbl E type
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The MTRR gene encodes methionine synthase reductase (<a href="https://enzyme.expasy.org/EC/2.1.1.135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.1.1.135</a>). Methionine is an essential amino acid in mammals. It is required for protein synthesis and is a central player in 1-carbon metabolism. In its activated form, S-adenosylmethionine (SAM), it is the methyl donor in hundreds of biologic transmethylation reactions and the donor of propylamine in polyamine synthesis. The eventual product of the demethylation of methionine is homocysteine, and its remethylation is catalyzed by a cobalamin-dependent enzyme, methionine synthase (MTR; <a href="/entry/156570">156570</a>). Over time, the cob(I)alamin cofactor of methionine synthase becomes oxidized to cob(II)alamin, rendering the MTR enzyme inactive. Regeneration of functional enzyme requires reductive methylation via a reaction catalyzed by MTRR in which SAM is used as a methyl donor (<a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 consensus sequences from bacteria to predict binding sites for FMN, FAD, and NADPH, <a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al. (1998)</a> cloned a cDNA corresponding to the 'methionine synthase reductase' reducing system required for maintenance of methionine synthase in a functional state. Northern blot analysis revealed that the gene, symbolized MTRR, is expressed as a predominant mRNA of 3.6 kb. The deduced protein, a novel member of the FNR family of electron transferases, contains 698 amino acids with a predicted molecular mass of 77.7 kD. The authenticity of the cDNA sequence was confirmed by identification of mutations in cblE patients, including a 4-bp frameshift in 2 affected sibs and a 3-bp deletion in a third patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 purified recombinant human proteins, <a href="#13" class="mim-tip-reference" title="Yamada, K., Gravel, R. A., Toraya, T., Matthews, R. G. <strong>Human methionine synthase reductase is a molecular chaperone for human methionine synthase.</strong> Proc. Nat. Acad. Sci. 103: 9476-9481, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16769880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0603694103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769880">Yamada et al. (2006)</a> found that MSR maintained MTR activity at a 1:1 stoichiometric ratio. In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced due to stabilization of apoMS in the presence of MSR. MSR was also able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, which stimulated conversion of apoMS and aquacobalamin to holoMS. <a href="#13" class="mim-tip-reference" title="Yamada, K., Gravel, R. A., Toraya, T., Matthews, R. G. <strong>Human methionine synthase reductase is a molecular chaperone for human methionine synthase.</strong> Proc. Nat. Acad. Sci. 103: 9476-9481, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16769880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0603694103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769880">Yamada et al. (2006)</a> concluded that MSR serves as a chaperone for MS and as an aquacobalamin reductase, rather than acting solely in reductive activation of MS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16769880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al. (1998)</a> mapped the MTRR gene to chromosome 5p15.3-p15.2 by a combination of somatic cell hybrid analysis and fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; <a href="/entry/236270">236270</a>), originally reported by <a href="#9" class="mim-tip-reference" title="Schuh, S., Rosenblatt, D. S., Cooper, B. A., Schroeder, M.-L., Bishop, A. J., Seargeant, L. E., Haworth, J. C. <strong>Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy.</strong> New Eng. J. Med. 310: 686-690, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6700644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6700644</a>] [<a href="https://doi.org/10.1056/NEJM198403153101104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6700644">Schuh et al. (1984)</a> and <a href="#8" class="mim-tip-reference" title="Rosenblatt, D. S., Cooper, B. A., Schmutz, S. M., Zaleski, W. A., Casey, R. E. <strong>Prenatal vitamin B-12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease).</strong> Lancet 325: 1127-1129, 1985. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2860337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2860337</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)92433-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2860337">Rosenblatt et al. (1985)</a>, <a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al. (1998)</a> identified a heterozygous truncating mutation in the MTRR gene (<a href="#0001">602568.0001</a>). A second mutation was not found. Another unrelated patient carried a different truncation mutation (<a href="#0002">602568.0002</a>); a second mutation was not found. The disorder, which is a defect of cobalamin metabolism, was characterized by megaloblastic anemia, developmental delay, hyperhomocysteinemia, and hypomethioninemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6700644+2860337+9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RT-PCR, heteroduplex, single-strand conformation polymorphism (SSCP), and DNA sequence analyses <a href="#11" class="mim-tip-reference" title="Wilson, A., Leclerc, D., Rosenblatt, D. S., Gravel, R. A. <strong>Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism.</strong> Hum. Molec. Genet. 8: 2009-2016, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10484769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10484769</a>] [<a href="https://doi.org/10.1093/hmg/8.11.2009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10484769">Wilson et al. (1999)</a> identified 11 mutations in 8 patients from 7 families belonging to the cblE complementation group of patients with defects in methionine synthase reductase. The mutations included splicing defects that led to large insertions or deletions, as well as a number of smaller deletions and point mutations. Apart from an intronic substitution found in 2 unrelated patients, the mutations appeared singular among individuals. Of the 11, 3 were nonsense mutations, allowing for the identification of 2 patients for whom little if any MSR protein should be produced. The remaining 8 involved point mutations or in-frame disruptions of the coding sequence and were distributed throughout the coding region. The data demonstrated a unique requirement for MSR in reductive activation of methionine synthase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10484769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. <strong>CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families.</strong> J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12555939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12555939</a>] [<a href="https://doi.org/10.1023/a:1021299117308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12555939">Zavadakova et al. (2002)</a> identified 3 novel mutations (<a href="#0004">602568.0004</a>-<a href="#0006">602568.0006</a>) in the MTRR gene causing cblE type homocystinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 gene-trap techniques, <a href="#7" class="mim-tip-reference" title="Padmanabhan, N., Jia, D., Geary-Joo, C., Wu, X., Ferguson-Smith, A. C., Fung, E., Bieda, M. C., Snyder, F. F., Gravel, R. A., Cross, J. C., Watson, E. D. <strong>Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.</strong> Cell 155: 81-93, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24074862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24074862</a>] [<a href="https://doi.org/10.1016/j.cell.2013.09.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24074862">Padmanabhan et al. (2013)</a> created a hypomorphic mutation in the mouse Mtrr gene that resulted in increased plasma homocysteine, an indicator of folate deficiency. The Mtrr mutation resulted in intrauterine growth restriction, developmental delay, and congenital malformation, including neural tube, heart, and placental defects. However, these effects did not correlate with the embryonic Mtrr genotypes, but rather with the Mtrr genotypes of the maternal grandparents. Mtrr deficiency in either maternal grandparent was sufficient to cause defects in grandprogeny at embryonic day 10.5. Mtrr deficiency caused tissue-specific global DNA hypomethylation. The authors observed widespread epigenetic instability associated with altered gene expression in wildtype grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments showed that Mtrr deficiency led to 2 distinct, separable phenotypes: adverse effects on the uterine environment of their wildtype daughters, leading to growth defects in wildtype grandprogeny, and the appearance of congenital malformations, independent of maternal environment, that persisted for 5 generations. <a href="#7" class="mim-tip-reference" title="Padmanabhan, N., Jia, D., Geary-Joo, C., Wu, X., Ferguson-Smith, A. C., Fung, E., Bieda, M. C., Snyder, F. F., Gravel, R. A., Cross, J. C., Watson, E. D. <strong>Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.</strong> Cell 155: 81-93, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24074862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24074862</a>] [<a href="https://doi.org/10.1016/j.cell.2013.09.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24074862">Padmanabhan et al. (2013)</a> proposed that hypomorphic mutations in the MTRR gene associated with reduced expression may lead to congenital abnormalities, even with normal dietary folate. Moreover, the transgenerational effect of MTRR deficiency may only be overcome by folate fortification for more than 1 generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24074862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; <a href="/entry/236270">236270</a>), originally reported by <a href="#9" class="mim-tip-reference" title="Schuh, S., Rosenblatt, D. S., Cooper, B. A., Schroeder, M.-L., Bishop, A. J., Seargeant, L. E., Haworth, J. C. <strong>Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy.</strong> New Eng. J. Med. 310: 686-690, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6700644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6700644</a>] [<a href="https://doi.org/10.1056/NEJM198403153101104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6700644">Schuh et al. (1984)</a> and <a href="#8" class="mim-tip-reference" title="Rosenblatt, D. S., Cooper, B. A., Schmutz, S. M., Zaleski, W. A., Casey, R. E. <strong>Prenatal vitamin B-12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease).</strong> Lancet 325: 1127-1129, 1985. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2860337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2860337</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)92433-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2860337">Rosenblatt et al. (1985)</a>, <a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al. (1998)</a> used RT-PCR-dependent heteroduplex analysis and sequencing to identify a heterozygous 1675del4 deletion in the MTRR gene, resulting in a frameshift and nearby stop codon. A second mutation was not found. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6700644+2860337+9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2126812944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2126812944;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=rs2126812944" 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=rs2126812944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (<a href="/entry/236270">236270</a>), <a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al. (1998)</a> identified a 1726delTTG mutation that resulted in the loss of a highly conserved leucine at position 576 of the amino acid sequence of the protein product. This mutation was present in heterozygous state. On direct sequencing of the PCR products, only a very faint background contributed by the allele that showed no abnormality on heteroduplex analysis was observed, suggesting that the other, unidentified mutation in this patient was associated with a very low level of steady-state mRNA. This patient had originally been reported by <a href="#10" class="mim-tip-reference" title="Tauro, G. P., Danks, D. M., Rowe, P. B., Van der Weyden, M. B., Schwarz, M. A., Collins, V. L., Neal, B. W. <strong>Dihydrofolate reductase deficiency causing megaloblastic anemia in two families.</strong> New Eng. J. Med. 294: 466-470, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1060915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1060915</a>] [<a href="https://doi.org/10.1056/NEJM197602262940903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1060915">Tauro et al. (1976)</a> as having dihydrofolate reductase deficiency (<a href="/entry/613839">613839</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9501215+1060915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs1801394 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1801394;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/rs1801394?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=rs1801394" 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=rs1801394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The cloning of the cDNA for MTRR (<a href="#5" class="mim-tip-reference" title="Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. <strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong> Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.6.3059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501215">Leclerc et al., 1998</a>) led to the identification of a 66A-G polymorphism, resulting in an ile22-to-met (I22M) substitution, that was shown by <a href="#12" class="mim-tip-reference" title="Wilson, A., Platt, R., Wu, Q., Leclerc, D., Christensen, B., Yang, H., Gravel, R. A., Rozen, R. <strong>A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.</strong> Molec. Genet. Metab. 67: 317-323, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10444342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10444342</a>] [<a href="https://doi.org/10.1006/mgme.1999.2879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10444342">Wilson et al. (1999)</a> to be associated with increased risk for the neural tube defect spina bifida (see <a href="/entry/601634">601634</a>). Serum deficiency of vitamin B12 increased the effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10444342+9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hobbs, C. A., Sherman, S. L., Yi, P., Hopkins, S. E., Torfs, C. P., Hine, R. J., Pogribna, M., Rozen, R., James, S. J. <strong>Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.</strong> Am. J. Hum. Genet. 67: 623-630, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10930360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10930360</a>] [<a href="https://doi.org/10.1086/303055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10930360">Hobbs et al. (2000)</a> evaluated the frequencies of the MTHFR 677C-T (<a href="/entry/607093#0003">607093.0003</a>) and MTRR 66A-G polymorphisms in DNA samples from 157 mothers of children with Down syndrome (<a href="/entry/190685">190685</a>) and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results were consistent with the preliminary observations of <a href="#4" class="mim-tip-reference" title="James, S. J., Pogribna, M., Pogribny, I. P., Melnyk, S., Hine, R. J., Gibson, J. B., Yi, P., Tafoya, D. L., Swenson, D. H., Wilson, V. L., Gaylor, D. W. <strong>Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.</strong> Am. J. Clin. Nutr. 70: 495-501, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10500018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10500018</a>] [<a href="https://doi.org/10.1093/ajcn/70.4.495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10500018">James et al. (1999)</a> that the MTHFR 677C-T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio (OR) of 1.91 (95% CI, 1.19-3.05). In addition, the homozygous MTRR 66A-G polymorphism was independently associated with a 2.57-fold increase in estimated risk (95% CI, 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an OR of 4.08 (95% CI, 1.94-8.56). The 2 polymorphisms appeared to act without a multiplicative interaction. The association between folate deficiency and DNA hypomethylation lent support to the possibility that the increased frequency of the MTHFR and MTTR polymorphisms observed in this study may be associated with chromosomal nondisjunction and Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10930360+10500018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Doolin, M.-T., Barbaux, S., McDonnell, M., Hoess, K., Whitehead, A. S., Mitchell, L. E. <strong>Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.</strong> Am. J. Hum. Genet. 71: 1222-1226, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12375236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12375236</a>] [<a href="https://doi.org/10.1086/344209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12375236">Doolin et al. (2002)</a> studied the potential involvement of both the maternal and embryonic genotypes in determining risk of spina bifida. Analysis of data on this polymorphism and the A2756G polymorphism of the methionine synthase gene (<a href="/entry/156570#0008">156570.0008</a>) provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants the risk of having a child with spina bifida appeared to increase with the number of high-risk alleles in the maternal genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12375236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bosco, P., Gueant-Rodriguez, R. M., Anello, G., Barone, C., Namour, F., Caraci, F., Romano, A., Romano, C., Gueant, J. L. <strong>Methionine synthase (MTR) 2756 (A-G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are 3 risk factors for having a child with Down syndrome.</strong> Am. J. Med. Genet. 121A: 219-224, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923861</a>] [<a href="https://doi.org/10.1002/ajmg.a.20234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12923861">Bosco et al. (2003)</a> studied the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C, <a href="/entry/607093#0004">607093.0004</a>), methionine synthase (MTR 2756A-G), and methionine synthase reductase (MTRR 66A-G) on the risk of being a Down syndrome (<a href="/entry/190685">190685</a>) case or of having a child with Down syndrome (case mother). Plasma homocysteine and other factors were likewise studied. They found that after adjustment for age, total homocysteine and MTR 2756 AG/GG genotype were significant risk factors for having a Down syndrome child, with odds ratio (OR) of 6.7 and 3.5, respectively. The MTR 2756 AG/GG genotype increased significantly the risk of being a Down syndrome case, with an OR of 3.8. Double heterozygosity for MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a Down syndrome child, with an OR estimated at 5.0, after adjustment for total homocysteine level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12923861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="O'Leary, V. B., Mills, J. L., Pangilinan, F., Kirke, P. N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J. M., Parle-McDermott, A., Molloy, A. M., Brody, L. C. <strong>Members of the Birth Defects Research Group: Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association.</strong> Molec. Genet. Metab. 85: 220-227, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15979034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15979034</a>] [<a href="https://doi.org/10.1016/j.ymgme.2005.02.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15979034">O'Leary et al. (2005)</a> found no association between the 66A-G polymorphism and neural tube defects in an Irish population comprising 470 patients and 447 mothers of cases. A dominant paternal effect was observed (OR of 1.46). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15979034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 20-year-old woman with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (<a href="/entry/236270">236270</a>) who presented with megaloblastic anemia at 10 weeks of age, <a href="#15" class="mim-tip-reference" title="Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. <strong>CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families.</strong> J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12555939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12555939</a>] [<a href="https://doi.org/10.1023/a:1021299117308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12555939">Zavadakova et al. (2002)</a> identified compound heterozygosity for a G-to-A transition at nucleotide 1459 of the MTRR gene on one allele, leading to a glycine-to-arginine substitution at codon 487 (G487R), and a 2-bp insertion on the other allele (see <a href="#0005">602568.0005</a>). The patient was treated with folates and vitamin B12, and subsequent attempts to cease administration of folates led to recurrence of megaloblastic anemia. Biochemical features included severe hyperhomocysteinemia and hypomethioninemia and, in fibroblasts, defective formation of methionine from formate, and no complementation with cblE cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The second mutation of the compound heterozygous patient reported by <a href="#15" class="mim-tip-reference" title="Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. <strong>CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families.</strong> J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12555939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12555939</a>] [<a href="https://doi.org/10.1023/a:1021299117308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12555939">Zavadakova et al. (2002)</a> (see <a href="#0004">602568.0004</a>) was a 2-bp insertion after nucleotide 1623 of the MTRR gene (1623-1624insTA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs893229476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs893229476;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/rs893229476?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=rs893229476" 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=rs893229476" 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=RCV000820217 OR RCV001532026 OR RCV002537460 OR RCV003467497" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000820217, RCV001532026, RCV002537460, RCV003467497" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000820217...</a>
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<p><a href="#15" class="mim-tip-reference" title="Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. <strong>CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families.</strong> J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12555939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12555939</a>] [<a href="https://doi.org/10.1023/a:1021299117308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12555939">Zavadakova et al. (2002)</a> reported an 8-year-old girl with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (<a href="/entry/236270">236270</a>) in whom megaloblastic anemia was detected at 11 weeks of age. She had nystagmus, hyperkinesis, and developmental delay that resolved with age. Severe hyperhomocysteinemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cobalamin E defect. The patient was homozygous for a 140-bp insertion (903-904ins140). The insertion was caused by a T-to-C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. Both the patients' parents originated from the same geographic region, and the family history pointed to possible consanguinity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wilson, A., Leclerc, D., Rosenblatt, D. S., Gravel, R. A. <strong>Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism.</strong> Hum. Molec. Genet. 8: 2009-2016, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10484769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10484769</a>] [<a href="https://doi.org/10.1093/hmg/8.11.2009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10484769">Wilson et al. (1999)</a> identified this mutation in 2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10484769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION 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> rs137853062 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853062;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/rs137853062?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=rs137853062" 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=rs137853062" 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=RCV000007449 OR RCV000757493 OR RCV002512874 OR RCV003460434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007449, RCV000757493, RCV002512874, RCV003460434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007449...</a>
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<p>In a group of 9 patients of European origin with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (<a href="/entry/236270">236270</a>), <a href="#14" class="mim-tip-reference" title="Zavadakova, P., Fowler, B., Suormala, T., Novotna, Z., Mueller, P., Hennermann, J. B., Zeman, J., Vilaseca, M. A., Vilarinho, L., Gutsche, S., Wilichowski, E., Horneff, G., Kozich, V. <strong>cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.</strong> Hum. Mutat. 25: 239-247, 2005. Note: Erratum: Hum. Mutat. 26: 590 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15714522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15714522</a>] [<a href="https://doi.org/10.1002/humu.20131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15714522">Zavadakova et al. (2005)</a> found a 1361C-T transition in the MTRR gene causing a ser454-to-leu (S454L) substitution in 5 independent alleles, either in a homozygous state (2 patients) or a heterozygous state (1 patient). The S454L mutation had been found only in patients of Spanish or Portuguese ancestry, supporting the idea that this is an Iberian mutation. The 2 homozygous patients were mildly affected without severe neurologic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15714522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Bosco, P., Gueant-Rodriguez, R. M., Anello, G., Barone, C., Namour, F., Caraci, F., Romano, A., Romano, C., Gueant, J. L.
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<strong>Methionine synthase (MTR) 2756 (A-G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are 3 risk factors for having a child with Down syndrome.</strong>
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Am. J. Med. Genet. 121A: 219-224, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923861</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12923861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20234" target="_blank">Full Text</a>]
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Doolin, M.-T., Barbaux, S., McDonnell, M., Hoess, K., Whitehead, A. S., Mitchell, L. E.
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<strong>Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.</strong>
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Am. J. Hum. Genet. 71: 1222-1226, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12375236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12375236</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12375236" 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/10.1086/344209" target="_blank">Full Text</a>]
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Hobbs, C. A., Sherman, S. L., Yi, P., Hopkins, S. E., Torfs, C. P., Hine, R. J., Pogribna, M., Rozen, R., James, S. J.
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<strong>Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.</strong>
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Am. J. Hum. Genet. 67: 623-630, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10930360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10930360</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10930360" 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/10.1086/303055" target="_blank">Full Text</a>]
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James, S. J., Pogribna, M., Pogribny, I. P., Melnyk, S., Hine, R. J., Gibson, J. B., Yi, P., Tafoya, D. L., Swenson, D. H., Wilson, V. L., Gaylor, D. W.
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<strong>Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.</strong>
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Am. J. Clin. Nutr. 70: 495-501, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10500018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10500018</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10500018" 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/ajcn/70.4.495" target="_blank">Full Text</a>]
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Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A.
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<strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong>
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Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501215[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=9501215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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O'Leary, V. B., Mills, J. L., Pangilinan, F., Kirke, P. N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J. M., Parle-McDermott, A., Molloy, A. M., Brody, L. C.
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<strong>Members of the Birth Defects Research Group: Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15979034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15979034</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15979034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2005.02.003" target="_blank">Full Text</a>]
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Padmanabhan, N., Jia, D., Geary-Joo, C., Wu, X., Ferguson-Smith, A. C., Fung, E., Bieda, M. C., Snyder, F. F., Gravel, R. A., Cross, J. C., Watson, E. D.
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<strong>Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.</strong>
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Cell 155: 81-93, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24074862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24074862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24074862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2013.09.002" target="_blank">Full Text</a>]
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Rosenblatt, D. S., Cooper, B. A., Schmutz, S. M., Zaleski, W. A., Casey, R. E.
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<strong>Prenatal vitamin B-12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease).</strong>
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Lancet 325: 1127-1129, 1985. Note: Originally Volume I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2860337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2860337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2860337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(85)92433-x" target="_blank">Full Text</a>]
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Schuh, S., Rosenblatt, D. S., Cooper, B. A., Schroeder, M.-L., Bishop, A. J., Seargeant, L. E., Haworth, J. C.
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<strong>Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy.</strong>
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New Eng. J. Med. 310: 686-690, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6700644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6700644</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6700644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM198403153101104" target="_blank">Full Text</a>]
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Tauro, G. P., Danks, D. M., Rowe, P. B., Van der Weyden, M. B., Schwarz, M. A., Collins, V. L., Neal, B. W.
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<strong>Dihydrofolate reductase deficiency causing megaloblastic anemia in two families.</strong>
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New Eng. J. Med. 294: 466-470, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1060915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1060915</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1060915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM197602262940903" target="_blank">Full Text</a>]
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Wilson1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, A., Leclerc, D., Rosenblatt, D. S., Gravel, R. A.
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|
<strong>Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism.</strong>
|
|
Hum. Molec. Genet. 8: 2009-2016, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10484769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10484769</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10484769" 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/8.11.2009" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Wilson1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, A., Platt, R., Wu, Q., Leclerc, D., Christensen, B., Yang, H., Gravel, R. A., Rozen, R.
|
|
<strong>A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.</strong>
|
|
Molec. Genet. Metab. 67: 317-323, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10444342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10444342</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10444342" 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/10.1006/mgme.1999.2879" 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="13" class="mim-anchor"></a>
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<a id="Yamada2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamada, K., Gravel, R. A., Toraya, T., Matthews, R. G.
|
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<strong>Human methionine synthase reductase is a molecular chaperone for human methionine synthase.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 9476-9481, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16769880[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=16769880" 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/10.1073/pnas.0603694103" 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="14" class="mim-anchor"></a>
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<a id="Zavadakova2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zavadakova, P., Fowler, B., Suormala, T., Novotna, Z., Mueller, P., Hennermann, J. B., Zeman, J., Vilaseca, M. A., Vilarinho, L., Gutsche, S., Wilichowski, E., Horneff, G., Kozich, V.
|
|
<strong>cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.</strong>
|
|
Hum. Mutat. 25: 239-247, 2005. Note: Erratum: Hum. Mutat. 26: 590 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15714522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15714522</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15714522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20131" 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="15" class="mim-anchor"></a>
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<a id="Zavadakova2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V.
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<strong>CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families.</strong>
|
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J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12555939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12555939</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12555939" 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/10.1023/a:1021299117308" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<br />
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 12/06/2017
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 7/26/2006<br>Patricia A. Hartz - updated : 7/19/2006<br>Victor A. McKusick - updated : 1/6/2006<br>Victor A. McKusick - updated : 4/1/2005<br>Victor A. McKusick - updated : 10/7/2003<br>Ada Hamosh - updated : 9/18/2003<br>Victor A. McKusick - updated : 12/23/2002<br>Victor A. McKusick - updated : 9/25/2000<br>Victor A. McKusick - updated : 10/25/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 4/24/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 12/06/2017
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/12/2013<br>ckniffin : 7/11/2013<br>terry : 1/20/2010<br>alopez : 5/30/2007<br>carol : 10/18/2006<br>carol : 7/31/2006<br>ckniffin : 7/26/2006<br>mgross : 7/20/2006<br>terry : 7/19/2006<br>alopez : 6/9/2006<br>wwang : 1/17/2006<br>terry : 1/6/2006<br>wwang : 4/14/2005<br>wwang : 4/5/2005<br>terry : 4/1/2005<br>carol : 5/5/2004<br>alopez : 10/7/2003<br>alopez : 10/7/2003<br>alopez : 10/7/2003<br>alopez : 10/7/2003<br>alopez : 9/18/2003<br>tkritzer : 1/3/2003<br>tkritzer : 12/26/2002<br>terry : 12/23/2002<br>terry : 11/8/2000<br>mcapotos : 10/5/2000<br>mcapotos : 9/29/2000<br>terry : 9/25/2000<br>mgross : 11/3/1999<br>terry : 10/25/1999<br>carol : 4/29/1998<br>carol : 4/28/1998<br>carol : 4/25/1998
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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 class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602568
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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METHIONINE SYNTHASE REDUCTASE; MTRR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MSR
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MTRR</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1296847007;
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</span>
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</p>
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<div>
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<br />
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 5p15.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:7,850,859-7,901,113 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<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-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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5p15.31
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Neural tube defects, folate-sensitive, susceptibility to}
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</span>
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</td>
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<td>
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<span class="mim-font">
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601634
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Homocystinuria-megaloblastic anemia, cbl E type
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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236270
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The MTRR gene encodes methionine synthase reductase (EC 2.1.1.135). Methionine is an essential amino acid in mammals. It is required for protein synthesis and is a central player in 1-carbon metabolism. In its activated form, S-adenosylmethionine (SAM), it is the methyl donor in hundreds of biologic transmethylation reactions and the donor of propylamine in polyamine synthesis. The eventual product of the demethylation of methionine is homocysteine, and its remethylation is catalyzed by a cobalamin-dependent enzyme, methionine synthase (MTR; 156570). Over time, the cob(I)alamin cofactor of methionine synthase becomes oxidized to cob(II)alamin, rendering the MTR enzyme inactive. Regeneration of functional enzyme requires reductive methylation via a reaction catalyzed by MTRR in which SAM is used as a methyl donor (Leclerc et al., 1998). </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>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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|
<p>Using consensus sequences from bacteria to predict binding sites for FMN, FAD, and NADPH, Leclerc et al. (1998) cloned a cDNA corresponding to the 'methionine synthase reductase' reducing system required for maintenance of methionine synthase in a functional state. Northern blot analysis revealed that the gene, symbolized MTRR, is expressed as a predominant mRNA of 3.6 kb. The deduced protein, a novel member of the FNR family of electron transferases, contains 698 amino acids with a predicted molecular mass of 77.7 kD. The authenticity of the cDNA sequence was confirmed by identification of mutations in cblE patients, including a 4-bp frameshift in 2 affected sibs and a 3-bp deletion in a third patient. </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">
|
|
<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">
|
|
<p>Using purified recombinant human proteins, Yamada et al. (2006) found that MSR maintained MTR activity at a 1:1 stoichiometric ratio. In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced due to stabilization of apoMS in the presence of MSR. MSR was also able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, which stimulated conversion of apoMS and aquacobalamin to holoMS. Yamada et al. (2006) concluded that MSR serves as a chaperone for MS and as an aquacobalamin reductase, rather than acting solely in reductive activation of MS. </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">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>Leclerc et al. (1998) mapped the MTRR gene to chromosome 5p15.3-p15.2 by a combination of somatic cell hybrid analysis and fluorescence in situ hybridization. </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>In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; 236270), originally reported by Schuh et al. (1984) and Rosenblatt et al. (1985), Leclerc et al. (1998) identified a heterozygous truncating mutation in the MTRR gene (602568.0001). A second mutation was not found. Another unrelated patient carried a different truncation mutation (602568.0002); a second mutation was not found. The disorder, which is a defect of cobalamin metabolism, was characterized by megaloblastic anemia, developmental delay, hyperhomocysteinemia, and hypomethioninemia. </p><p>By RT-PCR, heteroduplex, single-strand conformation polymorphism (SSCP), and DNA sequence analyses Wilson et al. (1999) identified 11 mutations in 8 patients from 7 families belonging to the cblE complementation group of patients with defects in methionine synthase reductase. The mutations included splicing defects that led to large insertions or deletions, as well as a number of smaller deletions and point mutations. Apart from an intronic substitution found in 2 unrelated patients, the mutations appeared singular among individuals. Of the 11, 3 were nonsense mutations, allowing for the identification of 2 patients for whom little if any MSR protein should be produced. The remaining 8 involved point mutations or in-frame disruptions of the coding sequence and were distributed throughout the coding region. The data demonstrated a unique requirement for MSR in reductive activation of methionine synthase. </p><p>Zavadakova et al. (2002) identified 3 novel mutations (602568.0004-602568.0006) in the MTRR gene causing cblE type homocystinuria. </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>Using gene-trap techniques, Padmanabhan et al. (2013) created a hypomorphic mutation in the mouse Mtrr gene that resulted in increased plasma homocysteine, an indicator of folate deficiency. The Mtrr mutation resulted in intrauterine growth restriction, developmental delay, and congenital malformation, including neural tube, heart, and placental defects. However, these effects did not correlate with the embryonic Mtrr genotypes, but rather with the Mtrr genotypes of the maternal grandparents. Mtrr deficiency in either maternal grandparent was sufficient to cause defects in grandprogeny at embryonic day 10.5. Mtrr deficiency caused tissue-specific global DNA hypomethylation. The authors observed widespread epigenetic instability associated with altered gene expression in wildtype grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments showed that Mtrr deficiency led to 2 distinct, separable phenotypes: adverse effects on the uterine environment of their wildtype daughters, leading to growth defects in wildtype grandprogeny, and the appearance of congenital malformations, independent of maternal environment, that persisted for 5 generations. Padmanabhan et al. (2013) proposed that hypomorphic mutations in the MTRR gene associated with reduced expression may lead to congenital abnormalities, even with normal dietary folate. Moreover, the transgenerational effect of MTRR deficiency may only be overcome by folate fortification for more than 1 generation. </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>7 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 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION 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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MTRR, 4-BP DEL, NT1675
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<br />
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ClinVar: RCV000007442
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; 236270), originally reported by Schuh et al. (1984) and Rosenblatt et al. (1985), Leclerc et al. (1998) used RT-PCR-dependent heteroduplex analysis and sequencing to identify a heterozygous 1675del4 deletion in the MTRR gene, resulting in a frameshift and nearby stop codon. A second mutation was not found. </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 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION 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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MTRR, 3-BP DEL, 1726TTG
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<br />
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SNP: rs2126812944,
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ClinVar: RCV000007443
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270), Leclerc et al. (1998) identified a 1726delTTG mutation that resulted in the loss of a highly conserved leucine at position 576 of the amino acid sequence of the protein product. This mutation was present in heterozygous state. On direct sequencing of the PCR products, only a very faint background contributed by the allele that showed no abnormality on heteroduplex analysis was observed, suggesting that the other, unidentified mutation in this patient was associated with a very low level of steady-state mRNA. This patient had originally been reported by Tauro et al. (1976) as having dihydrofolate reductase deficiency (613839). </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 NEURAL TUBE DEFECTS, FOLATE-SENSITIVE, SUSCEPTIBILITY TO</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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DOWN SYNDROME, SUSCEPTIBILITY TO, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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MTRR, ILE22MET
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<br />
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SNP: rs1801394,
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gnomAD: rs1801394,
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ClinVar: RCV000007444, RCV000007445, RCV000126873, RCV000144926, RCV000264714, RCV001274255, RCV003482129, RCV004716905
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>The cloning of the cDNA for MTRR (Leclerc et al., 1998) led to the identification of a 66A-G polymorphism, resulting in an ile22-to-met (I22M) substitution, that was shown by Wilson et al. (1999) to be associated with increased risk for the neural tube defect spina bifida (see 601634). Serum deficiency of vitamin B12 increased the effect. </p><p>Hobbs et al. (2000) evaluated the frequencies of the MTHFR 677C-T (607093.0003) and MTRR 66A-G polymorphisms in DNA samples from 157 mothers of children with Down syndrome (190685) and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results were consistent with the preliminary observations of James et al. (1999) that the MTHFR 677C-T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio (OR) of 1.91 (95% CI, 1.19-3.05). In addition, the homozygous MTRR 66A-G polymorphism was independently associated with a 2.57-fold increase in estimated risk (95% CI, 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an OR of 4.08 (95% CI, 1.94-8.56). The 2 polymorphisms appeared to act without a multiplicative interaction. The association between folate deficiency and DNA hypomethylation lent support to the possibility that the increased frequency of the MTHFR and MTTR polymorphisms observed in this study may be associated with chromosomal nondisjunction and Down syndrome. </p><p>Doolin et al. (2002) studied the potential involvement of both the maternal and embryonic genotypes in determining risk of spina bifida. Analysis of data on this polymorphism and the A2756G polymorphism of the methionine synthase gene (156570.0008) provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants the risk of having a child with spina bifida appeared to increase with the number of high-risk alleles in the maternal genotype. </p><p>Bosco et al. (2003) studied the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C, 607093.0004), methionine synthase (MTR 2756A-G), and methionine synthase reductase (MTRR 66A-G) on the risk of being a Down syndrome (190685) case or of having a child with Down syndrome (case mother). Plasma homocysteine and other factors were likewise studied. They found that after adjustment for age, total homocysteine and MTR 2756 AG/GG genotype were significant risk factors for having a Down syndrome child, with odds ratio (OR) of 6.7 and 3.5, respectively. The MTR 2756 AG/GG genotype increased significantly the risk of being a Down syndrome case, with an OR of 3.8. Double heterozygosity for MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a Down syndrome child, with an OR estimated at 5.0, after adjustment for total homocysteine level. </p><p>O'Leary et al. (2005) found no association between the 66A-G polymorphism and neural tube defects in an Irish population comprising 470 patients and 447 mothers of cases. A dominant paternal effect was observed (OR of 1.46). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
MTRR, GLY487ARG
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|
<br />
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|
|
SNP: rs137853061,
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|
|
ClinVar: RCV000007446, RCV000210727, RCV003460433, RCV004700198
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 20-year-old woman with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270) who presented with megaloblastic anemia at 10 weeks of age, Zavadakova et al. (2002) identified compound heterozygosity for a G-to-A transition at nucleotide 1459 of the MTRR gene on one allele, leading to a glycine-to-arginine substitution at codon 487 (G487R), and a 2-bp insertion on the other allele (see 602568.0005). The patient was treated with folates and vitamin B12, and subsequent attempts to cease administration of folates led to recurrence of megaloblastic anemia. Biochemical features included severe hyperhomocysteinemia and hypomethioninemia and, in fibroblasts, defective formation of methionine from formate, and no complementation with cblE cells. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTRR, 2-BP INS, 1623TA
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|
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<br />
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|
|
SNP: rs2126808021,
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|
|
|
ClinVar: RCV000007447
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>The second mutation of the compound heterozygous patient reported by Zavadakova et al. (2002) (see 602568.0004) was a 2-bp insertion after nucleotide 1623 of the MTRR gene (1623-1624insTA). </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>.0006 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
MTRR, 140-BP INS, NT903
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|
<br />
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|
|
SNP: rs893229476,
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|
|
|
gnomAD: rs893229476,
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|
|
|
ClinVar: RCV000820217, RCV001532026, RCV002537460, RCV003467497
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Zavadakova et al. (2002) reported an 8-year-old girl with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270) in whom megaloblastic anemia was detected at 11 weeks of age. She had nystagmus, hyperkinesis, and developmental delay that resolved with age. Severe hyperhomocysteinemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cobalamin E defect. The patient was homozygous for a 140-bp insertion (903-904ins140). The insertion was caused by a T-to-C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. Both the patients' parents originated from the same geographic region, and the family history pointed to possible consanguinity. </p><p>Wilson et al. (1999) identified this mutation in 2 patients. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
MTRR, SER454LEU
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<br />
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SNP: rs137853062,
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|
gnomAD: rs137853062,
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|
|
ClinVar: RCV000007449, RCV000757493, RCV002512874, RCV003460434
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a group of 9 patients of European origin with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270), Zavadakova et al. (2005) found a 1361C-T transition in the MTRR gene causing a ser454-to-leu (S454L) substitution in 5 independent alleles, either in a homozygous state (2 patients) or a heterozygous state (1 patient). The S454L mutation had been found only in patients of Spanish or Portuguese ancestry, supporting the idea that this is an Iberian mutation. The 2 homozygous patients were mildly affected without severe neurologic involvement. </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>REFERENCES</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Bosco, P., Gueant-Rodriguez, R. M., Anello, G., Barone, C., Namour, F., Caraci, F., Romano, A., Romano, C., Gueant, J. L.
|
|
<strong>Methionine synthase (MTR) 2756 (A-G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are 3 risk factors for having a child with Down syndrome.</strong>
|
|
Am. J. Med. Genet. 121A: 219-224, 2003.
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[PubMed: 12923861]
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[Full Text: https://doi.org/10.1002/ajmg.a.20234]
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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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Doolin, M.-T., Barbaux, S., McDonnell, M., Hoess, K., Whitehead, A. S., Mitchell, L. E.
|
|
<strong>Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.</strong>
|
|
Am. J. Hum. Genet. 71: 1222-1226, 2002.
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[PubMed: 12375236]
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[Full Text: https://doi.org/10.1086/344209]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hobbs, C. A., Sherman, S. L., Yi, P., Hopkins, S. E., Torfs, C. P., Hine, R. J., Pogribna, M., Rozen, R., James, S. J.
|
|
<strong>Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.</strong>
|
|
Am. J. Hum. Genet. 67: 623-630, 2000.
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[PubMed: 10930360]
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[Full Text: https://doi.org/10.1086/303055]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
James, S. J., Pogribna, M., Pogribny, I. P., Melnyk, S., Hine, R. J., Gibson, J. B., Yi, P., Tafoya, D. L., Swenson, D. H., Wilson, V. L., Gaylor, D. W.
|
|
<strong>Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.</strong>
|
|
Am. J. Clin. Nutr. 70: 495-501, 1999.
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[PubMed: 10500018]
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[Full Text: https://doi.org/10.1093/ajcn/70.4.495]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A.
|
|
<strong>Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 3059-3064, 1998.
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|
[PubMed: 9501215]
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