Divergent phenotypes in siblings with identical novel mutations in the HNF-1α gene leading to maturity onset diabetes of the young type 3

Abstract

Background: Maturity onset diabetes of the young (MODY) is an autosomal dominant form of non-insulin-dependent diabetes mellitus caused by mutations in at least 13 different genes. The hepatocyte nuclear factor (HNF)-1α gene is affected in the most common form (HNF1A-MODY [MODY3]).

Case presentation: We describe the co-inheritance of a novel heterozygous missense mutation c.1761C > G (p.Pro588Ala) with a novel complex deletion insertion mutation (c.1765_1766delinsGCCCGfs86*) in the HNF-1α gene among affected members of one family. Both mutations were present in the affected patients and neither was present in unaffected family members. The family had not only inheritance of MODY but also increased susceptibility to type 2 diabetes. Therefore one family member had classical type 2 diabetes including metabolic syndrome aggravated by a genetic predisposition in the form of HNF1A-MODY.

Conclusion: The presence of common type 2 diabetes features should not detract from the possibility of MODY in patients with a striking autosomal-dominant family history.

Keywords: HNF-1α; HNF1A-MODY; Maturity-onset diabetes of the young; Metabolic challenge; Metabolic syndrome; Phenotype variety.

Fig. 1

Co-segregation of the mutations and key clinical characteristics. a A heterozygous mutation (c.1761C > G (p.Pro588Ala)) and a complex deletion insertion mutation (c.1765_1766delinsGCCCGfs86*) in exon 9 of the HNF-1α gene were identified by direct sequencing (upper panel: control, middle patient forward strand, below: patient reverse strand). Horizontal arrows indicate direction of sequencing; vertical arrows indicate sequence alterations. b Co-segregation of the HNF-1α mutations in the family. The genetic status, age of onset of diabetes, current therapy and date of birth are indicated. Numbers indicate the index patient and the brother. (Black symbol: early onset diabetes phenotype; grey symbol: late onset type 2 diabetes NM: heterozygous mutation present; NN: no mutation; INS: insulin; OHA: oral hypoglycemic agents; SU: sulfonylurea). In detail, at time of investigation the medication was as follows: index patient (insulin, angiotensin-converting-enzyme inhibitors), brother (glinide), daughter (metformin), father (insulin, statin, glibenclamide), and mother (metformin, glibenclamide, statin, angiotensin-converting-enzyme inhibitors)