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<title>
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Entry
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- #606392 - MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4; MODY4
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- OMIM
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<span class="h4">#606392</span>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(MATURITY-ONSET DIABETES OF THE YOUNG, TYPE) OR (PDX1)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8028&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK500456/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4509" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606392[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><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=552" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div style="display: table-cell;">Animal Models</div>
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</a>
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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/disease/DOID:0111103" 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="http://www.informatics.jax.org/disease/606392" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA002552/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></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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<a id="title" class="mim-anchor"></a>
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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> 609571007<br />
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<strong>ORPHA:</strong> 552<br />
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<strong>DO:</strong> 0111103<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="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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606392
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</span>
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</span>
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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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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4; MODY4
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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">
|
|
MODY, TYPE 4
|
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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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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene 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 table-hover 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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<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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<p>A number sign (#) is used with this entry because of evidence that MODY type 4 (MODY4) is caused by heterozygous mutation in the IPF1 gene (PDX1; <a href="/entry/600733">600733</a>) on chromosome 13q12.</p><p>For a phenotypic description and discussion of genetic heterogeneity of MODY, see <a href="/entry/606391">606391</a>.</p>
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<p>Mutation in the IPF1 (PDX1) gene is a rare cause of MODY (<a href="#3" class="mim-tip-reference" title="Fajans, S. S., Bell, G. I., Polonsky, K. S. <strong>Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.</strong> New Eng. J. Med. 345: 971-980, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11575290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11575290</a>] [<a href="https://doi.org/10.1056/NEJMra002168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11575290">Fajans et al., 2001</a>). In a consanguineous family, originally reported by <a href="#7" class="mim-tip-reference" title="Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L. <strong>Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.</strong> Am. J. Dis. Child. 147: 607-609, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506821</a>] [<a href="https://doi.org/10.1001/archpedi.1993.02160300013005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506821">Wright et al. (1993)</a>, in which an infant with pancreatic agenesis (<a href="/entry/260370">260370</a>) was homozygous for a 1-bp deletion in the PDX1 gene (<a href="/entry/600733#0001">600733.0001</a>), <a href="#4" class="mim-tip-reference" title="Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F. <strong>Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter)</strong> Nature Genet. 17: 138-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326926</a>] [<a href="https://doi.org/10.1038/ng1097-138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326926">Stoffers et al. (1997)</a> found that members heterozygous for this mutation had early-onset type 2 diabetes mellitus, which they designated MODY4. The expression of diabetes in this family may occur at later ages than in families with other types of MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326926+11575290+8506821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the course of expressing the mutant IPF1 protein (<a href="#4" class="mim-tip-reference" title="Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F. <strong>Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter)</strong> Nature Genet. 17: 138-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326926</a>] [<a href="https://doi.org/10.1038/ng1097-138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326926">Stoffers et al., 1997</a>) in eukaryotic cells, <a href="#5" class="mim-tip-reference" title="Stoffers, D. A., Stanojevic, V., Habener, J. F. <strong>Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.</strong> J. Clin. Invest. 102: 232-241, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649577</a>] [<a href="https://doi.org/10.1172/JCI2242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649577">Stoffers et al. (1998)</a> detected a second IPF1 isoform, recognized by C-terminal but not N-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the N-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the C-terminal DNA-binding domain but lacks the transactivation domain. The C-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta-cell-specific genes regulated by the mutant IPF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326926+9649577" 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="Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S. <strong>Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation.</strong> Pediat. Diabetes 10: 492-496, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19496967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19496967</a>] [<a href="https://doi.org/10.1111/j.1399-5448.2009.00526.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19496967">Thomas et al. (2009)</a> reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene identified by <a href="#4" class="mim-tip-reference" title="Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F. <strong>Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter)</strong> Nature Genet. 17: 138-141, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326926</a>] [<a href="https://doi.org/10.1038/ng1097-138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326926">Stoffers et al. (1997)</a> (<a href="/entry/600733#0001">600733.0001</a>) in a similar family. <a href="#6" class="mim-tip-reference" title="Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S. <strong>Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation.</strong> Pediat. Diabetes 10: 492-496, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19496967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19496967</a>] [<a href="https://doi.org/10.1111/j.1399-5448.2009.00526.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19496967">Thomas et al. (2009)</a> suggested that the 2 families might be related. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326926+19496967" 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="Fajans, S. S., Bell, G. I., Paz, V. P., Below, J. E., Cox, N. J., Martin, C., Thomas, I. H., Chen, M. <strong>Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60.</strong> Transl. Res. 156: 7-14, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20621032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20621032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20621032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.trsl.2010.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20621032">Fajans et al. (2010)</a> identified a single 2.5-Mb region on chromosome 13 shared by a Michigan-Kentucky pedigree originally reported by <a href="#6" class="mim-tip-reference" title="Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S. <strong>Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation.</strong> Pediat. Diabetes 10: 492-496, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19496967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19496967</a>] [<a href="https://doi.org/10.1111/j.1399-5448.2009.00526.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19496967">Thomas et al. (2009)</a> and a Virginia pedigree, originally reported by <a href="#7" class="mim-tip-reference" title="Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L. <strong>Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.</strong> Am. J. Dis. Child. 147: 607-609, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506821</a>] [<a href="https://doi.org/10.1001/archpedi.1993.02160300013005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506821">Wright et al. (1993)</a>, both of which carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands, and that a complex pedigree structure connected the 2 probands. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19496967+8506821+20621032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reclassified Variants</em></strong></p><p>
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The E224K mutation (<a href="/entry/600733#0007">600733.0007</a>) in the IPF1 gene that was identified in patients with maturity-onset diabetes of the young type 4 by <a href="#1" class="mim-tip-reference" title="Cockburn, B. N., Bermano, G., Boodram, L.-L. G., Teelucksingh, S., Tsuchiya, T., Mahabir, D., Allan, A. B., Stein, R., Docherty, K., Bell, G. I. <strong>Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.</strong> J. Clin. Endocr. Metab. 89: 971-978, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764823</a>] [<a href="https://doi.org/10.1210/jc.2003-031282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764823">Cockburn et al. (2004)</a> has been reclassified as a variant of unknown significance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764823" 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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Cockburn, B. N., Bermano, G., Boodram, L.-L. G., Teelucksingh, S., Tsuchiya, T., Mahabir, D., Allan, A. B., Stein, R., Docherty, K., Bell, G. I.
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<strong>Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.</strong>
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J. Clin. Endocr. Metab. 89: 971-978, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764823</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764823" 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/10.1210/jc.2003-031282" target="_blank">Full Text</a>]
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Fajans, S. S., Bell, G. I., Paz, V. P., Below, J. E., Cox, N. J., Martin, C., Thomas, I. H., Chen, M.
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<strong>Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60.</strong>
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Transl. Res. 156: 7-14, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20621032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20621032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20621032[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=20621032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Fajans, S. S., Bell, G. I., Polonsky, K. S.
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New Eng. J. Med. 345: 971-980, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11575290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11575290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11575290" 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/NEJMra002168" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Stoffers1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F.
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<strong>Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter)</strong>
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Nature Genet. 17: 138-141, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1097-138" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Stoffers1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stoffers, D. A., Stanojevic, V., Habener, J. F.
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<strong>Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.</strong>
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J. Clin. Invest. 102: 232-241, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649577</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649577" 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/10.1172/JCI2242" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Thomas2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S.
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<strong>Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation.</strong>
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Pediat. Diabetes 10: 492-496, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19496967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19496967</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19496967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-5448.2009.00526.x" target="_blank">Full Text</a>]
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<a id="Wright1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L.
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<strong>Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.</strong>
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Am. J. Dis. Child. 147: 607-609, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506821</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506821" 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/10.1001/archpedi.1993.02160300013005" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 02/23/2012
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 4/19/2010
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 10/17/2001
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<span class="mim-text-font">
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carol : 01/16/2024
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<span class="mim-text-font">
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carol : 02/23/2012<br>wwang : 4/5/2011<br>wwang : 9/21/2010<br>terry : 4/19/2010<br>terry : 2/19/2009<br>alopez : 12/29/2005<br>carol : 4/24/2002<br>carol : 10/18/2001
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<span class="mim-font">
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<strong>#</strong> 606392
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4; MODY4
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<em>Alternative titles; symbols</em>
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MODY, TYPE 4
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<strong>SNOMEDCT:</strong> 609571007;
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<strong>ORPHA:</strong> 552;
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<strong>DO:</strong> 0111103;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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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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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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13q12.2
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</span>
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<span class="mim-font">
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MODY, type IV
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<span class="mim-font">
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606392
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<span class="mim-font">
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3
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<span class="mim-font">
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PDX1
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<span class="mim-font">
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600733
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that MODY type 4 (MODY4) is caused by heterozygous mutation in the IPF1 gene (PDX1; 600733) on chromosome 13q12.</p><p>For a phenotypic description and discussion of genetic heterogeneity of MODY, see 606391.</p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>Mutation in the IPF1 (PDX1) gene is a rare cause of MODY (Fajans et al., 2001). In a consanguineous family, originally reported by Wright et al. (1993), in which an infant with pancreatic agenesis (260370) was homozygous for a 1-bp deletion in the PDX1 gene (600733.0001), Stoffers et al. (1997) found that members heterozygous for this mutation had early-onset type 2 diabetes mellitus, which they designated MODY4. The expression of diabetes in this family may occur at later ages than in families with other types of MODY. </p><p>In the course of expressing the mutant IPF1 protein (Stoffers et al., 1997) in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by C-terminal but not N-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the N-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the C-terminal DNA-binding domain but lacks the transactivation domain. The C-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta-cell-specific genes regulated by the mutant IPF1. </p><p>Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene identified by Stoffers et al. (1997) (600733.0001) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related. </p><p>Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by a Michigan-Kentucky pedigree originally reported by Thomas et al. (2009) and a Virginia pedigree, originally reported by Wright et al. (1993), both of which carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands, and that a complex pedigree structure connected the 2 probands. </p><p><strong><em>Reclassified Variants</em></strong></p><p>
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The E224K mutation (600733.0007) in the IPF1 gene that was identified in patients with maturity-onset diabetes of the young type 4 by Cockburn et al. (2004) has been reclassified as a variant of unknown significance. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Cockburn, B. N., Bermano, G., Boodram, L.-L. G., Teelucksingh, S., Tsuchiya, T., Mahabir, D., Allan, A. B., Stein, R., Docherty, K., Bell, G. I.
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<strong>Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.</strong>
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J. Clin. Endocr. Metab. 89: 971-978, 2004.
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[PubMed: 14764823]
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[Full Text: https://doi.org/10.1210/jc.2003-031282]
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<li>
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<p class="mim-text-font">
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Fajans, S. S., Bell, G. I., Paz, V. P., Below, J. E., Cox, N. J., Martin, C., Thomas, I. H., Chen, M.
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<strong>Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60.</strong>
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Transl. Res. 156: 7-14, 2010.
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[PubMed: 20621032]
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[Full Text: https://doi.org/10.1016/j.trsl.2010.03.003]
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<p class="mim-text-font">
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Fajans, S. S., Bell, G. I., Polonsky, K. S.
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<strong>Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.</strong>
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New Eng. J. Med. 345: 971-980, 2001.
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[PubMed: 11575290]
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[Full Text: https://doi.org/10.1056/NEJMra002168]
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<li>
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<p class="mim-text-font">
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Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F.
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<strong>Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter)</strong>
|
|
Nature Genet. 17: 138-141, 1997.
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[PubMed: 9326926]
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[Full Text: https://doi.org/10.1038/ng1097-138]
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<p class="mim-text-font">
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Stoffers, D. A., Stanojevic, V., Habener, J. F.
|
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<strong>Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.</strong>
|
|
J. Clin. Invest. 102: 232-241, 1998.
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[PubMed: 9649577]
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[Full Text: https://doi.org/10.1172/JCI2242]
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</p>
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Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S.
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<strong>Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation.</strong>
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Pediat. Diabetes 10: 492-496, 2009.
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[PubMed: 19496967]
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[Full Text: https://doi.org/10.1111/j.1399-5448.2009.00526.x]
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Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L.
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<strong>Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.</strong>
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Am. J. Dis. Child. 147: 607-609, 1993.
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[PubMed: 8506821]
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[Full Text: https://doi.org/10.1001/archpedi.1993.02160300013005]
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Marla J. F. O'Neill - updated : 02/23/2012<br>Marla J. F. O'Neill - updated : 4/19/2010
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Ada Hamosh : 10/17/2001
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