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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. [ABSTRACT FROM AUTHOR]

Background: Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity., Aims: The aims of this study were the following: 1) to estimate the prevalence of MC4R mutations in obese Czech children; 2) to evaluate phenotypic features of the mutation carriers; 3) to compare weight, height, and body mass index of MC4R mutation carriers with noncarriers in longitudinal studies; 4) to determine the effect of a weight management program among MC4R mutation carriers; and 5) to perform a functional analysis of a novel variant., Subjects and Methods: We analyzed the coding region of MC4R in a cohort of 289 Czech children and adolescents with early-onset obesity by direct sequencing. Information on weight, height, body mass index, baseline biochemical data, and a weight loss follow-up study was obtained. In vitro functional analysis of one novel variant was performed., Results: We identified six different mutations in seven probands: one novel missense mutation Cys84Arg and five previously reported variants, Arg7Cys, Ser19fsdelA, Phe51Leu, Ser127Leu, and Gly181Asp. The Gly181Asp variant was detected in one homozygous carrier from unrelated parents. None of the mutation carriers fulfilled the MC4R syndrome criteria. A comparison of anthropometrics in mutation carriers and noncarriers during 13 yr of follow-up did not reveal any significant differences. MC4R mutation carriers exhibited a similar ability to lose weight as obese noncarriers. The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R., Conclusions: Among obese Czech children, we found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations and showed a similar response to diet management of MC4R mutation carriers and noncarriers.