Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations

Abstract

Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, Cinek O, Lebl J. Glucokinase diabetes in 103 families from a country‐based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Background: Glucokinase diabetes, also called GCK‐MODY or maturity‐onset diabetes of the young type 2 (MODY2), is caused by heterozygous mutations in the gene encoding glucokinase (GCK). Objective: The aim of study was to investigate the current prevalence of GCK mutations in a large cohort of Czech patients with typical clinical appearance of GCK‐MODY. In addition, we reanalyzed the negative results obtained previously by screening using the denaturing high‐performance liquid chromatography (dHPLC). Methods: We studied 140 unrelated Czech probands with clinical picture of GCK‐MODY who were referred to our center from the whole of the Czech Republic between the years 1999–2009 by direct sequencing of GCK gene. Results: A mutation in GCK was identified in 103 of 140 probands (74%). We identified 46 different GCK mutations of which 13 were novel. Several mutations were detected in multiple families: p.Glu40Lys (20 families), p.Gly318Arg (12), p.Leu315His (7) and p.Val33Ala (six families). Direct sequencing detected a GCK mutations in 9 of 20 previously dHPLC‐negative samples; the sensitivity of the dHPLC screening was calculated as 84%. Conclusions: The study shows a relatively high proportion of GCK mutations among individuals with GCK‐like phenotype, confirming the effectiveness of carefully applied clinical criteria prior to genetic testing. In the Czech MODY registry, GCK‐MODY represents the biggest subgroup of MODY (35%). We report several prevalent GCK mutations with a likely founder effect in the Czech population. Furthermore, our results provide ground for a possible recommendation to reinspect all negative results previously obtained by screening using dHPLC.