Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4α, GCK and HNF-1α

Abstract

Aims/hypothesis. The aim of this study was to examine the prevalence and nature of mutations in HNF4α/ MODY1, GCK/MODY2 and HNF-1α/MODY3 genes in Czech subjects with clinical diagnosis of MODY. Methods. We studied 61 unrelated index probands of Czech origin (28 males, 33 females) with a clinical diagnosis of MODY and 202 family members. The mean age of probands was 22.7±12.0 years (range, 6-62) and the mean age at the first recognition of hyperglycaemia was 14.7±6.0 years (range, 1-25). The promotor and coding regions inclusive intron exon boundaries of the HNF-4α, GCK and HNF-1α genes were examined by PCR-dHPLC (HNF-1α and GCK) and direct sequencing. Results. We identified 20 different mutations in the HNF-4α, GCK and HNF-1α in 29 families (48% of all families studied), giving a relative prevalence of 5% of MODY1, 31% of MODY2 and 11.5% of MODY3 among the Czech kindred with MODY. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4α, GCK and HNF-1α respectively, were new. Conclusion/interpretation. Of the families 48% carried mutations in the MODY1-3 genes and of the identified mutations 70% were new. In 52% of Czech families with clinical characteristics of MODY, no mutations were found in the analysed genes. This finding shows that the majority of MODY mutations in a central European population are local and that other MODY genes could be responsible for autosomal dominant transmission of diabetes mellitus. [Diabetologia (2003) 46:291-295] Keywords MODY, genetics, mutation, glucokinase, HNF-1α, HNF-4α, MODY X. Corresponding author: J. Lebl, Department of Paediatrics, 3rd Faculty of Medicine, Charles University, Vinohradska 159, 100 81 Prague 10, Czech Republic E-mail: lebl@fnkv.cz Abbreviations: GCK, Glucokinase; HNF-1α, hepatocyte nuclear factor-1alpha; HNF-4α, hepatocyte nuclear factor-4alpha; IPF-1 insulin promoter factor-1; HNF-1β, hepatocyte nuclear factor-1beta; dHPLC, denatured high performance liquid chromatography; RFLP, restriction fragment length polymorphism; OHA, oral hypoglycaemic agents. Six known MODY subtypes are caused by mutations in genes encoding the hepatocyte nuclear factor-4α (HNF-4α), glucokinase (GCK), hepatocyte nuclear factor-1α (HNF-1α), insulin promoter factor-1 (IPF-1), hepatocyte nuclear factor-1β (HNF-1β) and NeuroD1 respectively [1].The relative prevalence of distinct MODY subtypes differs substantially in studies in various populations [2,3,4], mutations in GCK representing from 8 to 63% and HNF-1α mutations for 13 to 64% of all subjects with MODY [5]. Mutations in the HNF-4α, IPF-1, HNF-1β and NeuroD1 have been recognised in single families only, while additional unknown MODY genes ("MODY X") may cause between 16 and 45% of cases of MODY [3].We initiated a study of genetic epidemiology of MODY in the Czech republic, as no data on the relaMaturity Onset Diabetes of the Young is a genetically heterogeneous form of diabetes mellitus, characterised by an autosomal dominant inheritance, by early age at onset and by a primary defect in beta-cell function.

A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

“…Mutation screening and genotyping. The mutation screening was performed by either denaturing high-performance liquid chromatography (20) or single-stranded conformation polymorphism-heteroduplex analysis (21). In our laboratory, these methodologies have an estimated sensitivity of Ͼ95% for detecting a variety of known mutations.…”

Common variants in MODY genes increase the risk of gestational diabetes mellitus

“…The most common forms of the disease are MODY2 and MODY3, which account for 20-65% of all MODY subtypes in Europe [10,11]. Mutations in the genes involved in MODY1 are less frequent and may account for 5% of subjects with MODY [10,11], while MODY4-6 are very rare [9,10].…”

Maturity onset diabetes of the young: Diagnosis and treatment options

“…The prevalence and incidence of MODY largely depends on the country and there are often new cases MODY diagnosed in the population [8]. The minimum prevalence of MODY was reported to be 1.1-4.2% of patients with diabetes or 2.4-4.6 cases per 100,000 [9][10][11][12][13][14][15][16].…”