Alternative titles; symbols
SNOMEDCT: 609562003; ORPHA: 552; DO: 0111099;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.12 | MODY, type I | 125850 | Autosomal dominant | 3 | HNF4A | 600281 |
A number sign (#) is used with this entry because of evidence that type 1 maturity-onset diabetes of the young (MODY) can be caused by mutation in the gene encoding hepatocyte nuclear factor-4-alpha (HNF4A; 600281) on chromosome 20.
Fajans et al. (2001) reported that mutation in the HNF4A gene is a relatively uncommon cause of MODY. They stated that only 13 families had been identified as having this form of MODY.
A specific missense mutation in the HNF4A gene (R76W; 600281.0008) causes MODY associated with Fanconi renotubular syndrome-4 (FRTS4; 616026).
In their review of MODY, Fajans et al. (2001) stated that, not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations in HNF4A (MODY1) and MODY due to mutations in the HNF1A gene (MODY3; 142410) are very similar since HNF4-alpha regulates the expression of HNF1-alpha (142410). 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 (MODY2; 125851). 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 many 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 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).
Most of the diabetic subjects in the well-studied R-W pedigree with MODY reported by Fajans (1989, 1990) had a reduced and delayed secretory response to glucose. A similar secretory response to glucose has been observed in many patients with late-age-of-onset forms of noninsulin-dependent diabetes mellitus (NIDDM) in the absence of islet-cell antibodies. Other MODY families have a 'hyperinsulinemic' response to glucose (Fajans, 1987) as is seen in the majority of NIDDM patients early in the natural history of their disease. Byrne et al. (1995) concluded that members of the R-W family who inherited the at-risk allele of the MODY1 gene have a characteristic pattern of altered insulin secretory responses to glucose. These alterations are present before the onset of hyperglycemia, suggesting a unique mechanism of beta-cell dysfunction different from the defect in MODY subjects with glucokinase mutation.
In the well-studied R-W pedigree with MODY reported by Fajans (1989, 1990), Bell et al. (1991) found linkage with a DNA polymorphism in the adenosine deaminase gene (608958); maximum lod = 5.25 at theta = 0.00. This places the MODY gene on chromosome 20q, probably in 20q13.
Bowden et al. (1992) reported an Edinburgh family and a Wisconsin family in which MODY was not linked to chromosome 20 markers. Furthermore, they observed a large multigeneration kindred in which early-onset noninsulin-dependent diabetes mellitus was linked to markers on chromosome 20 in one branch, whereas no linkage to chromosome 20 markers could be found in the NIDDM in 2 other branches.
Rothschild et al. (1993) reported multiple highly polymorphic markers in the 20q12-q13.1 region useful in the study of MODY families and in the further genetic and physical mapping of the region.
Stoffel et al. (1996) created a YAC contig consisting of 71 clones and spanning a region of about 18 Mb, which represents about 40% of the physical length of 20q. Using this physical map, they refined the location of MODY1 to a 13-cM interval (approximately 7 Mb) between D20S169 and D20S176.
The R-W pedigree, which included more than 360 members spanning 6 generations and 74 members with diabetes, including those with MODY, had been studied prospectively since 1958 (Fajans, 1989). The members of this family were descendants of a couple that immigrated from East Prussia to Detroit, Michigan in 1861 with their 4 sons, 3 of whom were diabetic, and 5 daughters, 1 of whom was diabetic. Linkage studies, as indicated earlier, showed that the gene responsible for MODY in this family is tightly linked to 20q12-q13.1. The demonstration that the gene for HNF1A (142410) is the site of mutations causing MODY3 prompted Yamagata et al. (1996) to screen the gene for HNF4A, which is known to map to chromosome 20, for a mutation in the R-W pedigree. A gln268-to-ter nonsense mutation was demonstrated (600281.0001).
Lindner et al. (1997) observed an R154X mutation in HNF4-alpha (600281.0002) in a 3-generation German family, Dresden-11. Lindner et al. (1997) reported no abnormalities in liver or renal function, despite severe diabetes requiring insulin or oral hypoglycemic agents, in 6 affected members of this pedigree. The phenotype was similar to that seen in the R-W pedigree. The results suggested to the authors that MODY1 is primarily a disorder of beta-cell function.
To determine the prevalence of MODY1, Moller et al. (1999) screened 10 Danish non-MODY3 probands for mutations in the minimal promoter and the 12 exons of the HNF4-alpha gene. They found a frameshift mutation (phe75fsdelT; 600281.0005) in 1 proband. They concluded that defects in the HNF4-alpha gene are a rare cause of MODY in Denmark.
Thomas et al. (2001) identified an alternative promoter of the HNF4-alpha gene, P2, which is 46 kb 5-prime to the previously identified P1 promoter of the human gene. Based on RT-PCR, this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, and is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter revealed functional binding sites for HNF1-alpha, HNF1-beta, and IPF1 (600733), the other transcription factors known to encode MODY genes. In a large MODY family, a mutated IPF1 binding site in the P2 promoter of the HNF4-alpha gene cosegregated with diabetes (lod score 3.25). The authors proposed a regulatory network of the 4 MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF4-alpha gene.
Pearson et al. (2007) studied 108 members of 15 families with MODY1 and found that birth weights were significantly higher in mutation carriers (p less than 0.001), with 30 (56%) of 54 mutation-positive infants being macrosomic compared to 7 (13%) of 54 mutation-negative infants (p less than 0.001). In addition, 8 of 54 mutation-positive infants had transient hypoglycemia versus none of the 54 mutation-negative infants (p = 0.003), and inappropriate hyperinsulinemia was documented in all 3 hypoglycemic cases tested (see, e.g., 600281.0007). The authors concluded that mutations in HNF4A are associated with increased birth weight and macrosomia, and that the natural history of MODY1 includes hyperinsulinemia at birth that evolves to decreased insulin secretion and diabetes later in life.
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.
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. GCK/MODY2 mutations were the most frequently found, in 41%: 7 novel and 2 theretofore described mutations. Four pedigrees (18%) harbored mutations in the HNF1A/MODY3 gene, including a previously unreported change. One family (4%) carried a novel mutation in the HNF4A gene (IVS5-2delA; 600281.0006), representing the first report of a MODY1 pedigree in the Spanish population. Clinical expression of MODY3 and MODY1 mutations, the second and third most frequent groups of defects found, was more severe, including the frequent development of chronic complications.
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Lindner, T., Gragnoli, C., Furuta, H., Cockburn, B. N., Petzold, C., Rietzsch, H., Weiss, U., Schulze, J., Bell, G. I. Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4-alpha/MODY1 gene. J. Clin. Invest. 100: 1400-1405, 1997. [PubMed: 9294105] [Full Text: https://doi.org/10.1172/JCI119660]
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