Co-inheritance of HNF1a and GCK Mutations in a Family With Maturity-Onset Diabetes of the Young (MODY)

Implications for Genetic Testing

M. P. López-Garrido; S. Herranz-Antolín; M. J. Alija-Merillas; P. Giralt; J. Escribano

Disclosures

Clin Endocrinol. 2013;79(3):342-347. 

In This Article

Abstract and Introduction

Abstract

Objective To determine the genetic basis of dominant early-onset diabetes mellitus in two families.

Patients and methods Molecular analysis by PCR sequencing of the promoter, the 5' untranslated region (UTR) and exons of both GCK and HNF1A genes was carried out in two families with clinically diagnosed dominant diabetes mellitus.

Results The novel HNF1A c.-154_-160TGGGGGT mutation, located in the 5' UTR, was present in several members of the two families in the heterozygous state. Interestingly, the GCK p.Y61X mutation was also identified in three members of one of the families, and two of them carried both mutations in heterozygosis. To the best of our knowledge, this is the first report of the co-inheritance of GCK and HNF1A mutations and the coexistence of maturity-onset diabetes of the young (MODY) 2, MODY 3 and unusual MODY 2–3 genotypes in the same family.

Conclusions Carriers of both GCK and HNF1A mutations manifested a typical MODY 3 phenotype and showed that the presence of a second mutation in the GCK gene apparently did not modify the clinical outcome, at least at the time of this study. Our data show that co-inheritance of MODY 2 and MODY 3 mutations should be considered, at least in some cases, for accurate genetic testing.

Introduction

Maturity-onset diabetes of the young (MODY) is a highly heterogeneous type of monogenic, noninsulin-dependent and nonketotic diabetes mellitus. It is characterized by early onset (usually before the age of 25 years) and is inherited as an autosomal dominant beta cell dysfunction.[1] Molecular genetics diagnosis is usually required to confirm the MODY phenotype. MODY 2 and MODY 3 are the most common forms of the disease, and together, they account for 20–65% of all the MODY types in Europe, although the reported prevalence varies across populations.[2,3] These two MODY types are caused by heterozygous loss-of-function mutations in the GLUCOKINASE (GCK) and HEPATOCYTE NUCLEAR FACTOR 1-ALFA (HNF1A) genes, respectively.[4] Clinical manifestations of MODY 2 are characterized by moderate raise in fasting glycaemia (6–7 mm; 100–125 mg/dl) usually from birth. Diabetes-associated complications are unlikely in MODY 2 patients, and they rarely need pharmacological treatment. HNF1A mutations cause mild fasting glucose impairment and usually originate higher 2-h glucose levels in oral glucose tolerance test (OGTT) than GCK mutations.[5] MODY 3 is usually diagnosed during adolescence or early adulthood, requires pharmacological treatment and frequently leads to late-onset microvascular complications.[6,7,8] Several hundred mutations have been identified in GCK and HNF1A genes (www.hgmd.org). Here, we identify a novel 5' untranslated region (5' UTR) HNF1A mutation in two MODY families, and as far as we know, we report for the first time, the co-inheritance of HNF1A and GCK mutations in two patients of the same family.

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