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Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report.

ABSTRACT: OBJECTIVE: We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes. RESEARCH DESIGN AND METHODS: A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy). RESULTS: The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation. CONCLUSIONS: MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia).

SUBMITTER: Forlani G

PROVIDER: S-EPMC2963490 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report.

Forlani Gabriele G Zucchini Stefano S Di Rocco Antonio A Di Luzio Raffaella R Scipione Mirella M Marasco Elena E Romeo Giovanni G Marchesini Giulio G Mantovani Vilma V

Diabetes care 20100812 11

<h4>Objective</h4>We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes.<h4>Research design and methods</h4>A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnanc ...[more]

PMID: 20705777

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Project description:BACKGROUND:Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS:We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS:HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.

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Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report.

Publications

Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report.

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