Maturity-Onset Diabetes Of The Young, Type 3

A number sign (#) is used with this entry because of evidence that maturity-onset diabetes of the young type 3 (MODY3) is caused by mutation in the hepatocyte nuclear factor-1-alpha gene (142410), which maps to chromosome 12q24.2.

MODY is a form of familial noninsulin-dependent diabetes mellitus (NIDDM; 125853) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance. For general information on MODY and on genetic heterogeneity in this disorder, see 606391.

In their review of MODY, Fajans et al. (2001) stated that, not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations in the HNF4A gene (MODY1) and MODY due to mutations in the HNF1A (MODY3) 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 to 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 I or type II 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).

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.

Ellard (2000) stated that 65 different mutations in the TCF1 gene had been found to cause MODY3 in a total of 116 families worldwide. They 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.

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.

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.

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.

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.

Yamagata et al. (1996) refined the localization of the MODY3 gene by a combination of genetic mapping and fluorescence in situ hybridization which localized the gene to 12q24.2.

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.

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.

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.