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<title>
Entry
- #600496 - MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3
- OMIM
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<span class="h4">#600496</span>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/600496"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 609570008<br />
<strong>ORPHA:</strong> 552<br />
<strong>DO:</strong> 0111102<br />
">ICD+</a>
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600496
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3
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<em>Alternative titles; symbols</em>
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MODY, TYPE 3
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Gene/Locus
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Gene/Locus <br /> MIM number
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<a href="/geneMap/12/887?start=-3&limit=10&highlight=887">
12q24.31
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<span class="mim-font">
MODY, type III
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<span class="mim-font">
<a href="/entry/600496"> 600496 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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HNF1A
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<a href="/entry/142410"> 142410 </a>
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<strong> Metabolic </strong>
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- Maturity-onset diabetes of the young (MODY) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/609561005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">609561005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342276&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342276</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004904" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004904</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004904" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004904</a>]</span><br /> - Noninsulin-dependent diabetes mellitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44054006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44054006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011860&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011860</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005978</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005978</a>]</span><br />
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<span class="h5 mim-font">
<strong> Misc </strong>
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- Early age of onset (under 25 years)<br />
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<strong> Lab </strong>
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<span class="mim-font">
- Hyperglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444780001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444780001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237598005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237598005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80394007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80394007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R73.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R73.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2919432&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2919432</a>, <a href="https://bioportal.bioontology.org/search?q=C0020456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020456</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003074</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003074</a>]</span><br /> - Severe insulin secretory defect <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775604&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775604</a>]</span><br />
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<span class="h5 mim-font">
<strong> Inheritance </strong>
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<span class="mim-font">
- Autosomal dominant (12q22-qter) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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<p>A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the hepatocyte nuclear factor-1-alpha gene (HNF1A; <a href="/entry/142410">142410</a>) on chromosome 12q24.</p>
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<p>MODY is a form of familial noninsulin-dependent diabetes mellitus (T2D; <a href="/entry/125853">125853</a>) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance.</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>In their review of MODY, <a href="#4" class="mim-tip-reference" title="Fajans, S. S., Bell, G. I., Polonsky, K. S. &lt;strong&gt;Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.&lt;/strong&gt; New Eng. J. Med. 345: 971-980, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11575290/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11575290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra002168&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11575290">Fajans et al. (2001)</a> stated that, not unexpectedly, the pathophysiologic mechanisms of MODY1 (<a href="/entry/125850">125850</a>) due to mutations in the HNF4A gene (<a href="/entry/600281">600281</a>) and MODY3 due to mutations in the HNF1A gene are very similar since HNF4-alpha regulates the expression of HNF1-alpha. Patients with mutations in these genes may present with a mild form of diabetes. Despite similarly mild elevations in fasting plasma glucose concentrations, patients with mutations in HNF4A or HNF1A have significantly higher plasma glucose concentrations 2 hours after glucose administration than do persons with glucokinase mutations. The hyperglycemia in patients with MODY1 and MODY3 tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in may of these patients (30-40% require insulin). These forms of MODY are associated with a progressive decrease in insulin secretion. In most populations, mutations in the HNF1A gene are the most common cause of MODY. Patients with MODY1 or MODY3 may have the full spectrum of complications of diabetes. Microvascular complications, particularly those involving the retina or kidneys, are as common in these patients as in patients with type 1 or type 2 diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are probably determined by the degree of glycemic control. Patients with MODY1 lose the glucose priming effect of mild hyperglycemia on insulin secretion. Both prediabetic and diabetic persons with mutations in the HNF4A gene secrete decreased amounts of insulin in response to glucose and in response to arginine and also have an impairment of glucagon secretion in response to arginine. Furthermore, a defect in the hypoglycemia-induced secretion of pancreatic polypeptide has been found in prediabetic and diabetic persons who have mutations in the gene for HNF4A. These findings suggested that a deficiency of HNF4A resulting from mutations in this gene may affect the function of the beta, alpha, and pancreatic polypeptide cells within pancreatic islets. Patients with mutations in HNF1A have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria. A deficiency of HNF4A affects triglyceride and apolipoprotein biosynthesis and is associated with a 50% reduction in serum triglyceride concentrations and a 25% reduction in serum concentrations of apolipoproteins AII and CIII and Lp(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'})"><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="#10" class="mim-tip-reference" title="Vaxillaire, M., Boccio, V., Philipi, A., Vigouroux, C., Terwilliger, J., Passa, P., Beckmann, J. S., Velho, G., Lathrop, G. M., Froguel, P. &lt;strong&gt;A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q.&lt;/strong&gt; Nature Genet. 9: 418-423, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7795649/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7795649&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0495-418&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7795649">Vaxillaire et al. (1995)</a> studied linkage in 12 French MODY families in which diabetes was not genetically linked to previously identified MODY loci. By a genomewide segregation analysis of highly informative microsatellite markers, they localized the gene for a MODY susceptibility locus (MODY3) to 12q in 6 families. The locus in question was thought to lie within a 7-cM interval bracketed by D12S86 and D12S342 (in 12q22-qter). The patients exhibited major hyperglycemia with a severe insulin (<a href="/entry/176730">176730</a>) secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795649" 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="Lesage, S, Hani, E. H., Philippi, A., Vaxillaire, M., Hager, J., Passa, P., Demenais, F., Froguel, P., Vionnet, N. &lt;strong&gt;Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM.&lt;/strong&gt; Diabetes 44: 1243-1247, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7556965/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7556965&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2337/diab.44.10.1243&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7556965">Lesage et al. (1995)</a> studied the possible implication of the MODY3 locus in late-onset NIDDM. In 600 affected sib pairs from 172 French families, linkage was rejected by all methods of analysis, implying that the MODY gene on 12q is not a major gene in late-onset NIDDM in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7556965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Menzel, S., Yamagata, K., Trabb, J. B., Nerup, J., Permutt, M. A., Fajans, S. S., Menzel, R., Iwasaki, N., Omori, Y., Cox, N. J., Bell, G. I. &lt;strong&gt;Localization of MODY3 to a 5-cM region of human chromosome 12.&lt;/strong&gt; Diabetes 44: 1408-1413, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7589847/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7589847&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2337/diab.44.12.1408&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7589847">Menzel et al. (1995)</a> found evidence of linkage to chromosome 12 in 3 families with MODY from Denmark, Germany, and the U.S. (Michigan) and suggestive evidence of linkage in a family from Japan. They placed the locus in a 5-cM interval between markers D12S86 and D12S807/D12S820. The age of onset of NIDDM was less than 25 years of age in the youngest generation in each pedigree and the segregation was consistent with autosomal dominant inheritance. In 1 pedigree, the body weight of 18 of 22 diabetic subjects was known and only 1 was obese. Diabetes was diagnosed in all but 1 of the subjects before 20 years of age. From the location of the linked markers the MODY3 locus was thought to be in the region 12q24.1-q24.32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7589847" 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="#7" class="mim-tip-reference" title="Mahtani, M. M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M. P., Weaver, A., Brettin, T., Duyk, G., Lander, E. S., Groop, L. C. &lt;strong&gt;Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.&lt;/strong&gt; Nature Genet. 14: 90-94, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782826/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8782826&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0996-90&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8782826">Mahtani et al. (1996)</a> screened over 4,000 individuals from a Swedish-speaking population isolate in western Finland and identified 26 families enriched for NIDDM. Families with the lowest insulin levels showed linkage to 12q24 near D12S1349. Unlike MODY3 families, the Finnish families with low insulin had an age of onset typical for NIDDM (mean = 58 years). <a href="#7" class="mim-tip-reference" title="Mahtani, M. M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M. P., Weaver, A., Brettin, T., Duyk, G., Lander, E. S., Groop, L. C. &lt;strong&gt;Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.&lt;/strong&gt; Nature Genet. 14: 90-94, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782826/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8782826&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0996-90&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8782826">Mahtani et al. (1996)</a> inferred the existence of a gene, NIDDM2 (<a href="/entry/601407">601407</a>), causing noninsulin-dependent diabetes mellitus associated with low insulin secretion and suggested that NIDDM2 and MODY3 may represent different alleles of the same gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782826" 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="Yamagata, K., Oda, N., Kalsaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R. D., Lathrop, G. M., Borhaj, V. V., Chen, X., Cox, N. J., Oda, Y., Yano, H., Le Beau, M. M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S. S., Hattersley, A. T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K. S., Turner, R. C., Velho, G., Chevre, J.-C., Froguel, P., Bell, G. I. &lt;strong&gt;Mutations in the hepatocyte nuclear factor-1-alpha gene in maturity-onset diabetes of the young (MODY3).&lt;/strong&gt; Nature 384: 455-457, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8945470/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8945470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/384455a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8945470">Yamagata et al. (1996)</a> refined the localization of the MODY3 locus by a combination of genetic mapping and fluorescence in situ hybridization which localized the gene to 12q24.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8945470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Lehto, M., Tuomi, T., Mahtani, M. M., Widen, E., Forsblom, C., Sarelin, L., Gullstrom, M., Isomaa, B., Lehtovirta, M., Hyrkko, A., Kanninen, T., Orho, M., Manley, S., Turner, R. C., Brettin, T., Kirby, A., Thomas, J., Duyk, G., Lander, E., Taskinen, M.-R., Groop, L. &lt;strong&gt;Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect.&lt;/strong&gt; J. Clin. Invest. 99: 582-591, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9045858/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9045858&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI119199&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9045858">Lehto et al. (1997)</a> analyzed the phenotype of affected members in 4 large Finnish MODY3 kindreds showing linkage to 12q with a maximum lod score of 15. They found evidence of severe impairment in insulin secretion, which was present also in those normal glycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with insulin-dependent diabetes mellitus by lack of glutamic acid decarboxylase antibodies. Taken together with the finding of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM, designated NIDDM2, as demonstrated by <a href="#7" class="mim-tip-reference" title="Mahtani, M. M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M. P., Weaver, A., Brettin, T., Duyk, G., Lander, E. S., Groop, L. C. &lt;strong&gt;Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.&lt;/strong&gt; Nature Genet. 14: 90-94, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782826/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8782826&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0996-90&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8782826">Mahtani et al. (1996)</a>, the data suggested to <a href="#5" class="mim-tip-reference" title="Lehto, M., Tuomi, T., Mahtani, M. M., Widen, E., Forsblom, C., Sarelin, L., Gullstrom, M., Isomaa, B., Lehtovirta, M., Hyrkko, A., Kanninen, T., Orho, M., Manley, S., Turner, R. C., Brettin, T., Kirby, A., Thomas, J., Duyk, G., Lander, E., Taskinen, M.-R., Groop, L. &lt;strong&gt;Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect.&lt;/strong&gt; J. Clin. Invest. 99: 582-591, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9045858/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9045858&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI119199&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9045858">Lehto et al. (1997)</a> that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response that subsequently progresses to diabetes, and underlines the importance of subphenotypic classification in studies of diabetes. MODY3 and NIDDM2 may be different alleles of the same gene; NIDDM2 has an average age of onset of 58 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8782826+9045858" 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="#3" class="mim-tip-reference" title="Ellard, S. &lt;strong&gt;Hepatocyte nuclear factor 1 alpha (HNF-1-alpha) mutations in maturity-onset diabetes of the young.&lt;/strong&gt; Hum. Mutat. 16: 377-385, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11058894/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11058894&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1098-1004(200011)16:5&lt;377::AID-HUMU1&gt;3.0.CO;2-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11058894">Ellard (2000)</a> noted that diagnostic and predictive genetic testing is possible for the majority of patients with MODY, opening new avenues for the classification, prediction, and perhaps eventually the prevention of diabetes in these families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058894" 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="#3" class="mim-tip-reference" title="Ellard, S. &lt;strong&gt;Hepatocyte nuclear factor 1 alpha (HNF-1-alpha) mutations in maturity-onset diabetes of the young.&lt;/strong&gt; Hum. Mutat. 16: 377-385, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11058894/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11058894&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1098-1004(200011)16:5&lt;377::AID-HUMU1&gt;3.0.CO;2-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11058894">Ellard (2000)</a> stated that 65 different mutations in the TCF1 (HNF1A) gene had been found to cause MODY3 in a total of 116 families worldwide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058894" 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="Aguilar-Salinas, C. A., Reyes-Rodriguez, E., Ordonez-Sanchez, M. L., Torres, M. A., Ramirez-Jimenez, S., Dominguez-Lopez, A., Martinez-Francois, J. R., Velasco-Perez, M. L., Alpizar, M., Garcia-Garcia, E., Gomez-Perez, F., Rull, J., Tusie-Luna, M. T. &lt;strong&gt;Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 220-226, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11232004/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11232004&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.1.7134&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11232004">Aguilar-Salinas et al. (2001)</a> investigated possible defects in the insulin sensitivity and the acute insulin response in a group of Mexican patients displaying early-onset NIDDM and evaluated the contribution of mutations in 3 of the genes linked to MODY. They studied 40 Mexican patients diagnosed between 20 and 40 years of age, in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to MODY was carried out by PCR-SSCP. Among this group they found 2 individuals carrying missense mutations in exon 4 of the HNF4A gene and 1 carrying a nonsense mutation in exon 7 of the HNF1A gene; 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. The authors concluded that a defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 years of age. Mutations in either the HNF1A or the HNF4A genes were present among the individuals who developed early-onset diabetes in their population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11232004" 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="#9" class="mim-tip-reference" title="Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A. &lt;strong&gt;Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.&lt;/strong&gt; Am. J. Hum. Genet. 109: 2018-2028, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36257325/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;36257325&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36257325[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2022.09.014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="36257325">Mirshahi et al. (2022)</a> comprehensively assessed the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK (<a href="/entry/138079">138079</a>) that account for more than 80% of monogenic diabetes. <a href="#9" class="mim-tip-reference" title="Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A. &lt;strong&gt;Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.&lt;/strong&gt; Am. J. Hum. Genet. 109: 2018-2028, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36257325/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;36257325&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36257325[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2022.09.014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="36257325">Mirshahi et al. (2022)</a> analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort of 132,194 individuals, and a UK population-based cohort of 198,748 individuals, and found that 1 in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts, highlighting the role of environment/ other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar (89 to 97%) across all cohorts. The authors suggested that for HNF1A and HNF4A, genetic interpretation and counseling should be tailored to the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36257325" 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="#2" class="mim-tip-reference" title="Barrio, R., Bellanne-Chantelot, C., Moreno, J. C., Morel, V., Calle, H., Alonso, M., Mustieles, C. &lt;strong&gt;Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.&lt;/strong&gt; J. Clin. Endocr. Metab. 87: 2532-2539, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12050210/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12050210&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.87.6.8530&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12050210">Barrio et al. (2002)</a> estimated the prevalence of major MODY subtypes in Spanish MODY families and analyzed genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the GCK (<a href="/entry/138079">138079</a>), HNF1A, and HNF4A genes using PCR-SSCP and/or direct sequencing. Mutations in MODY genes were identified in 64% of the families. Four pedigrees (18%) harbored mutations in the HNF1A/MODY3 gene, including a previously unreported change. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3 patients. Clinical expression of MODY3 and MODY1 mutations was more severe, including the frequent development of chronic complications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050210" 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>Population Genetics</strong>
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<p><a href="#4" class="mim-tip-reference" title="Fajans, S. S., Bell, G. I., Polonsky, K. S. &lt;strong&gt;Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.&lt;/strong&gt; New Eng. J. Med. 345: 971-980, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11575290/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11575290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra002168&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11575290">Fajans et al. (2001)</a> reported that mutations in the HNF1A gene have been identified in all racial and ethnic backgrounds, including European, Chinese, Japanese, African, and American Indian. Mutations in the HNF1A gene appear to be the most common cause of MODY among adults seen in diabetic clinics. <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'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Aguilar-Salinas2001" class="mim-anchor"></a>
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Aguilar-Salinas, C. A., Reyes-Rodriguez, E., Ordonez-Sanchez, M. L., Torres, M. A., Ramirez-Jimenez, S., Dominguez-Lopez, A., Martinez-Francois, J. R., Velasco-Perez, M. L., Alpizar, M., Garcia-Garcia, E., Gomez-Perez, F., Rull, J., Tusie-Luna, M. T.
<strong>Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population.</strong>
J. Clin. Endocr. Metab. 86: 220-226, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11232004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11232004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11232004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.86.1.7134" target="_blank">Full Text</a>]
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<a id="Barrio2002" class="mim-anchor"></a>
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Barrio, R., Bellanne-Chantelot, C., Moreno, J. C., Morel, V., Calle, H., Alonso, M., Mustieles, C.
<strong>Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.</strong>
J. Clin. Endocr. Metab. 87: 2532-2539, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050210</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.87.6.8530" target="_blank">Full Text</a>]
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<a id="Ellard2000" class="mim-anchor"></a>
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Ellard, S.
<strong>Hepatocyte nuclear factor 1 alpha (HNF-1-alpha) mutations in maturity-onset diabetes of the young.</strong>
Hum. Mutat. 16: 377-385, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058894</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1098-1004(200011)16:5&lt;377::AID-HUMU1&gt;3.0.CO;2-2" target="_blank">Full Text</a>]
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<a id="Fajans2001" class="mim-anchor"></a>
<div class="">
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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://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>]
[<a href="https://doi.org/10.1056/NEJMra002168" target="_blank">Full Text</a>]
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<a id="Lehto1997" class="mim-anchor"></a>
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Lehto, M., Tuomi, T., Mahtani, M. M., Widen, E., Forsblom, C., Sarelin, L., Gullstrom, M., Isomaa, B., Lehtovirta, M., Hyrkko, A., Kanninen, T., Orho, M., Manley, S., Turner, R. C., Brettin, T., Kirby, A., Thomas, J., Duyk, G., Lander, E., Taskinen, M.-R., Groop, L.
<strong>Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect.</strong>
J. Clin. Invest. 99: 582-591, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9045858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9045858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9045858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI119199" target="_blank">Full Text</a>]
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<a id="Lesage1995" class="mim-anchor"></a>
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Lesage, S, Hani, E. H., Philippi, A., Vaxillaire, M., Hager, J., Passa, P., Demenais, F., Froguel, P., Vionnet, N.
<strong>Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM.</strong>
Diabetes 44: 1243-1247, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7556965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7556965</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7556965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.2337/diab.44.10.1243" target="_blank">Full Text</a>]
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<a id="Mahtani1996" class="mim-anchor"></a>
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Mahtani, M. M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M. P., Weaver, A., Brettin, T., Duyk, G., Lander, E. S., Groop, L. C.
<strong>Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.</strong>
Nature Genet. 14: 90-94, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782826</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0996-90" target="_blank">Full Text</a>]
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<a id="Menzel1995" class="mim-anchor"></a>
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Menzel, S., Yamagata, K., Trabb, J. B., Nerup, J., Permutt, M. A., Fajans, S. S., Menzel, R., Iwasaki, N., Omori, Y., Cox, N. J., Bell, G. I.
<strong>Localization of MODY3 to a 5-cM region of human chromosome 12.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7589847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7589847</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7589847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.2337/diab.44.12.1408" target="_blank">Full Text</a>]
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<a id="Mirshahi2022" class="mim-anchor"></a>
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Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A.
<strong>Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.</strong>
Am. J. Hum. Genet. 109: 2018-2028, 2022.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36257325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36257325</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36257325[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=36257325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2022.09.014" target="_blank">Full Text</a>]
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<a id="Vaxillaire1995" class="mim-anchor"></a>
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Vaxillaire, M., Boccio, V., Philipi, A., Vigouroux, C., Terwilliger, J., Passa, P., Beckmann, J. S., Velho, G., Lathrop, G. M., Froguel, P.
<strong>A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q.</strong>
Nature Genet. 9: 418-423, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795649</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0495-418" target="_blank">Full Text</a>]
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<a id="Yamagata1996" class="mim-anchor"></a>
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Yamagata, K., Oda, N., Kalsaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R. D., Lathrop, G. M., Borhaj, V. V., Chen, X., Cox, N. J., Oda, Y., Yano, H., Le Beau, M. M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S. S., Hattersley, A. T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K. S., Turner, R. C., Velho, G., Chevre, J.-C., Froguel, P., Bell, G. I.
<strong>Mutations in the hepatocyte nuclear factor-1-alpha gene in maturity-onset diabetes of the young (MODY3).</strong>
Nature 384: 455-457, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8945470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8945470</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8945470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/384455a0" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 01/17/2023
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Marla J. F. O'Neill - updated : 04/19/2010<br>Marla J. F. O'Neill - updated : 5/6/2008<br>John A. Phillips, III - updated : 1/10/2003<br>Ada Hamosh - updated : 10/18/2001<br>John A. Phillips, III - updated : 9/29/2000<br>Victor A. McKusick - updated : 4/10/1997<br>Mark H. Paalman - updated : 9/10/1996
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Victor A. McKusick : 4/17/1995
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alopez : 01/17/2023
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carol : 12/08/2021<br>carol : 12/07/2021<br>terry : 04/19/2010<br>terry : 2/19/2009<br>carol : 6/3/2008<br>carol : 5/8/2008<br>terry : 5/6/2008<br>alopez : 1/10/2003<br>carol : 10/18/2001<br>carol : 5/30/2001<br>mgross : 10/3/2000<br>terry : 9/29/2000<br>dkim : 12/10/1998<br>mark : 4/10/1997<br>terry : 4/3/1997<br>mark : 12/4/1996<br>terry : 12/3/1996<br>mark : 9/10/1996<br>terry : 9/5/1996<br>mark : 2/1/1996<br>terry : 1/24/1996<br>joanna : 1/15/1996<br>mimadm : 11/3/1995<br>terry : 5/3/1995<br>terry : 4/18/1995<br>mark : 4/17/1995
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<strong>#</strong> 600496
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3
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<em>Alternative titles; symbols</em>
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MODY, TYPE 3
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<strong>SNOMEDCT:</strong> 609570008; &nbsp;
<strong>ORPHA:</strong> 552; &nbsp;
<strong>DO:</strong> 0111102; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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12q24.31
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MODY, type III
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600496
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Autosomal dominant
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3
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HNF1A
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142410
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the hepatocyte nuclear factor-1-alpha gene (HNF1A; 142410) on chromosome 12q24.</p>
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<strong>Description</strong>
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<p>MODY is a form of familial noninsulin-dependent diabetes mellitus (T2D; 125853) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance.</p><p>For a phenotypic description and discussion of genetic heterogeneity of MODY, see 606391.</p>
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<strong>Clinical Features</strong>
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<p>In their review of MODY, Fajans et al. (2001) stated that, not unexpectedly, the pathophysiologic mechanisms of MODY1 (125850) due to mutations in the HNF4A gene (600281) and MODY3 due to mutations in the HNF1A gene are very similar since HNF4-alpha regulates the expression of HNF1-alpha. Patients with mutations in these genes may present with a mild form of diabetes. Despite similarly mild elevations in fasting plasma glucose concentrations, patients with mutations in HNF4A or HNF1A have significantly higher plasma glucose concentrations 2 hours after glucose administration than do persons with glucokinase mutations. The hyperglycemia in patients with MODY1 and MODY3 tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in may of these patients (30-40% require insulin). These forms of MODY are associated with a progressive decrease in insulin secretion. In most populations, mutations in the HNF1A gene are the most common cause of MODY. Patients with MODY1 or MODY3 may have the full spectrum of complications of diabetes. Microvascular complications, particularly those involving the retina or kidneys, are as common in these patients as in patients with type 1 or type 2 diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are probably determined by the degree of glycemic control. Patients with MODY1 lose the glucose priming effect of mild hyperglycemia on insulin secretion. Both prediabetic and diabetic persons with mutations in the HNF4A gene secrete decreased amounts of insulin in response to glucose and in response to arginine and also have an impairment of glucagon secretion in response to arginine. Furthermore, a defect in the hypoglycemia-induced secretion of pancreatic polypeptide has been found in prediabetic and diabetic persons who have mutations in the gene for HNF4A. These findings suggested that a deficiency of HNF4A resulting from mutations in this gene may affect the function of the beta, alpha, and pancreatic polypeptide cells within pancreatic islets. Patients with mutations in HNF1A have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria. A deficiency of HNF4A affects triglyceride and apolipoprotein biosynthesis and is associated with a 50% reduction in serum triglyceride concentrations and a 25% reduction in serum concentrations of apolipoproteins AII and CIII and Lp(a). </p>
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<strong>Mapping</strong>
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<p>Vaxillaire et al. (1995) studied linkage in 12 French MODY families in which diabetes was not genetically linked to previously identified MODY loci. By a genomewide segregation analysis of highly informative microsatellite markers, they localized the gene for a MODY susceptibility locus (MODY3) to 12q in 6 families. The locus in question was thought to lie within a 7-cM interval bracketed by D12S86 and D12S342 (in 12q22-qter). The patients exhibited major hyperglycemia with a severe insulin (176730) secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function. </p><p>Lesage et al. (1995) studied the possible implication of the MODY3 locus in late-onset NIDDM. In 600 affected sib pairs from 172 French families, linkage was rejected by all methods of analysis, implying that the MODY gene on 12q is not a major gene in late-onset NIDDM in this population. </p><p>Menzel et al. (1995) found evidence of linkage to chromosome 12 in 3 families with MODY from Denmark, Germany, and the U.S. (Michigan) and suggestive evidence of linkage in a family from Japan. They placed the locus in a 5-cM interval between markers D12S86 and D12S807/D12S820. The age of onset of NIDDM was less than 25 years of age in the youngest generation in each pedigree and the segregation was consistent with autosomal dominant inheritance. In 1 pedigree, the body weight of 18 of 22 diabetic subjects was known and only 1 was obese. Diabetes was diagnosed in all but 1 of the subjects before 20 years of age. From the location of the linked markers the MODY3 locus was thought to be in the region 12q24.1-q24.32. </p><p>Mahtani et al. (1996) screened over 4,000 individuals from a Swedish-speaking population isolate in western Finland and identified 26 families enriched for NIDDM. Families with the lowest insulin levels showed linkage to 12q24 near D12S1349. Unlike MODY3 families, the Finnish families with low insulin had an age of onset typical for NIDDM (mean = 58 years). Mahtani et al. (1996) inferred the existence of a gene, NIDDM2 (601407), causing noninsulin-dependent diabetes mellitus associated with low insulin secretion and suggested that NIDDM2 and MODY3 may represent different alleles of the same gene. </p><p>Yamagata et al. (1996) refined the localization of the MODY3 locus by a combination of genetic mapping and fluorescence in situ hybridization which localized the gene to 12q24.2. </p><p>Lehto et al. (1997) analyzed the phenotype of affected members in 4 large Finnish MODY3 kindreds showing linkage to 12q with a maximum lod score of 15. They found evidence of severe impairment in insulin secretion, which was present also in those normal glycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with insulin-dependent diabetes mellitus by lack of glutamic acid decarboxylase antibodies. Taken together with the finding of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM, designated NIDDM2, as demonstrated by Mahtani et al. (1996), the data suggested to Lehto et al. (1997) that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response that subsequently progresses to diabetes, and underlines the importance of subphenotypic classification in studies of diabetes. MODY3 and NIDDM2 may be different alleles of the same gene; NIDDM2 has an average age of onset of 58 years. </p>
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<strong>Diagnosis</strong>
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<p>Ellard (2000) noted that diagnostic and predictive genetic testing is possible for the majority of patients with MODY, opening new avenues for the classification, prediction, and perhaps eventually the prevention of diabetes in these families. </p>
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<strong>Molecular Genetics</strong>
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<p>Ellard (2000) stated that 65 different mutations in the TCF1 (HNF1A) gene had been found to cause MODY3 in a total of 116 families worldwide. </p><p>Aguilar-Salinas et al. (2001) investigated possible defects in the insulin sensitivity and the acute insulin response in a group of Mexican patients displaying early-onset NIDDM and evaluated the contribution of mutations in 3 of the genes linked to MODY. They studied 40 Mexican patients diagnosed between 20 and 40 years of age, in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to MODY was carried out by PCR-SSCP. Among this group they found 2 individuals carrying missense mutations in exon 4 of the HNF4A gene and 1 carrying a nonsense mutation in exon 7 of the HNF1A gene; 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. The authors concluded that a defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 years of age. Mutations in either the HNF1A or the HNF4A genes were present among the individuals who developed early-onset diabetes in their population. </p><p>Mirshahi et al. (2022) comprehensively assessed the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK (138079) that account for more than 80% of monogenic diabetes. Mirshahi et al. (2022) analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort of 132,194 individuals, and a UK population-based cohort of 198,748 individuals, and found that 1 in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts, highlighting the role of environment/ other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar (89 to 97%) across all cohorts. The authors suggested that for HNF1A and HNF4A, genetic interpretation and counseling should be tailored to the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. </p>
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<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
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<p>Barrio et al. (2002) estimated the prevalence of major MODY subtypes in Spanish MODY families and analyzed genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the GCK (138079), HNF1A, and HNF4A genes using PCR-SSCP and/or direct sequencing. Mutations in MODY genes were identified in 64% of the families. Four pedigrees (18%) harbored mutations in the HNF1A/MODY3 gene, including a previously unreported change. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3 patients. Clinical expression of MODY3 and MODY1 mutations was more severe, including the frequent development of chronic complications. </p>
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<strong>Population Genetics</strong>
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<p>Fajans et al. (2001) reported that mutations in the HNF1A gene have been identified in all racial and ethnic backgrounds, including European, Chinese, Japanese, African, and American Indian. Mutations in the HNF1A gene appear to be the most common cause of MODY among adults seen in diabetic clinics. </p>
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
Aguilar-Salinas, C. A., Reyes-Rodriguez, E., Ordonez-Sanchez, M. L., Torres, M. A., Ramirez-Jimenez, S., Dominguez-Lopez, A., Martinez-Francois, J. R., Velasco-Perez, M. L., Alpizar, M., Garcia-Garcia, E., Gomez-Perez, F., Rull, J., Tusie-Luna, M. T.
<strong>Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population.</strong>
J. Clin. Endocr. Metab. 86: 220-226, 2001.
[PubMed: 11232004]
[Full Text: https://doi.org/10.1210/jcem.86.1.7134]
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<li>
<p class="mim-text-font">
Barrio, R., Bellanne-Chantelot, C., Moreno, J. C., Morel, V., Calle, H., Alonso, M., Mustieles, C.
<strong>Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.</strong>
J. Clin. Endocr. Metab. 87: 2532-2539, 2002.
[PubMed: 12050210]
[Full Text: https://doi.org/10.1210/jcem.87.6.8530]
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Ellard, S.
<strong>Hepatocyte nuclear factor 1 alpha (HNF-1-alpha) mutations in maturity-onset diabetes of the young.</strong>
Hum. Mutat. 16: 377-385, 2000.
[PubMed: 11058894]
[Full Text: https://doi.org/10.1002/1098-1004(200011)16:5&lt;377::AID-HUMU1&gt;3.0.CO;2-2]
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<p class="mim-text-font">
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: 11575290]
[Full Text: https://doi.org/10.1056/NEJMra002168]
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Lehto, M., Tuomi, T., Mahtani, M. M., Widen, E., Forsblom, C., Sarelin, L., Gullstrom, M., Isomaa, B., Lehtovirta, M., Hyrkko, A., Kanninen, T., Orho, M., Manley, S., Turner, R. C., Brettin, T., Kirby, A., Thomas, J., Duyk, G., Lander, E., Taskinen, M.-R., Groop, L.
<strong>Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect.</strong>
J. Clin. Invest. 99: 582-591, 1997.
[PubMed: 9045858]
[Full Text: https://doi.org/10.1172/JCI119199]
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Lesage, S, Hani, E. H., Philippi, A., Vaxillaire, M., Hager, J., Passa, P., Demenais, F., Froguel, P., Vionnet, N.
<strong>Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM.</strong>
Diabetes 44: 1243-1247, 1995.
[PubMed: 7556965]
[Full Text: https://doi.org/10.2337/diab.44.10.1243]
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Mahtani, M. M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., Chan, G., Daly, M., Forsblom, C., Kanninen, T., Kirby, A., Kruglyak, L., Munnelly, K., Parkkonen, M., Reeve-Daly, M. P., Weaver, A., Brettin, T., Duyk, G., Lander, E. S., Groop, L. C.
<strong>Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.</strong>
Nature Genet. 14: 90-94, 1996.
[PubMed: 8782826]
[Full Text: https://doi.org/10.1038/ng0996-90]
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<p class="mim-text-font">
Menzel, S., Yamagata, K., Trabb, J. B., Nerup, J., Permutt, M. A., Fajans, S. S., Menzel, R., Iwasaki, N., Omori, Y., Cox, N. J., Bell, G. I.
<strong>Localization of MODY3 to a 5-cM region of human chromosome 12.</strong>
Diabetes 44: 1408-1413, 1995.
[PubMed: 7589847]
[Full Text: https://doi.org/10.2337/diab.44.12.1408]
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<li>
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Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A.
<strong>Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.</strong>
Am. J. Hum. Genet. 109: 2018-2028, 2022.
[PubMed: 36257325]
[Full Text: https://doi.org/10.1016/j.ajhg.2022.09.014]
</p>
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<li>
<p class="mim-text-font">
Vaxillaire, M., Boccio, V., Philipi, A., Vigouroux, C., Terwilliger, J., Passa, P., Beckmann, J. S., Velho, G., Lathrop, G. M., Froguel, P.
<strong>A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q.</strong>
Nature Genet. 9: 418-423, 1995.
[PubMed: 7795649]
[Full Text: https://doi.org/10.1038/ng0495-418]
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Yamagata, K., Oda, N., Kalsaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R. D., Lathrop, G. M., Borhaj, V. V., Chen, X., Cox, N. J., Oda, Y., Yano, H., Le Beau, M. M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S. S., Hattersley, A. T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K. S., Turner, R. C., Velho, G., Chevre, J.-C., Froguel, P., Bell, G. I.
<strong>Mutations in the hepatocyte nuclear factor-1-alpha gene in maturity-onset diabetes of the young (MODY3).</strong>
Nature 384: 455-457, 1996.
[PubMed: 8945470]
[Full Text: https://doi.org/10.1038/384455a0]
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Contributors:
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<span class="mim-text-font">
Ada Hamosh - updated : 01/17/2023<br>Marla J. F. O&#x27;Neill - updated : 04/19/2010<br>Marla J. F. O&#x27;Neill - updated : 5/6/2008<br>John A. Phillips, III - updated : 1/10/2003<br>Ada Hamosh - updated : 10/18/2001<br>John A. Phillips, III - updated : 9/29/2000<br>Victor A. McKusick - updated : 4/10/1997<br>Mark H. Paalman - updated : 9/10/1996
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 4/17/1995
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Edit History:
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alopez : 01/17/2023<br>carol : 12/08/2021<br>carol : 12/07/2021<br>terry : 04/19/2010<br>terry : 2/19/2009<br>carol : 6/3/2008<br>carol : 5/8/2008<br>terry : 5/6/2008<br>alopez : 1/10/2003<br>carol : 10/18/2001<br>carol : 5/30/2001<br>mgross : 10/3/2000<br>terry : 9/29/2000<br>dkim : 12/10/1998<br>mark : 4/10/1997<br>terry : 4/3/1997<br>mark : 12/4/1996<br>terry : 12/3/1996<br>mark : 9/10/1996<br>terry : 9/5/1996<br>mark : 2/1/1996<br>terry : 1/24/1996<br>joanna : 1/15/1996<br>mimadm : 11/3/1995<br>terry : 5/3/1995<br>terry : 4/18/1995<br>mark : 4/17/1995
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