The most common etiology of non-syndromic monogenic obesity are mutations in gene for the Melanocortin-4 receptor (MC485) with variable prevalence in different countries (1.2-6.3 % of obese children). The aim of our study was 1) to search for MC4R mutations in obese children in Slovakia and compare their prevalence with other European countries, and 2) to describe the phenotype of the mutation carriers. DNA analysis by direct Sanger sequencing of the coding exons and intron/exon boundaries of the MC4R gene was performed in 268 unrelated Slovak children and adolescents with body mass index above the 97(th) percentile for age and sex and obesity onset up to 11 years (mean 4.3+/-2.8 years). Two different previously described heterozygous loss of function MC4R variants (i.e. p.Ser19Alafs*34, p.Ser127Leu) were identified in two obese probands, and one obese (p.Ser19Alafs*34), and one lean (p.Ser127Leu) adult family relatives. No loss of function variants were found in lean controls. The prevalence of loss-of-function MC4R variants in obese Slovak children was 0.7 %, what is one of the lowest frequencies in Europe.
- MeSH
- dítě MeSH
- fenotyp MeSH
- genotyp MeSH
- heterozygot MeSH
- lidé MeSH
- mladiství MeSH
- mutační analýza DNA MeSH
- obezita dětí a dospívajících genetika MeSH
- předškolní dítě MeSH
- receptor melanokortinový typ 4 genetika MeSH
- studie případů a kontrol MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Slovenská republika MeSH
AIMS/HYPOTHESIS: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). METHODS: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. RESULTS: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. CONCLUSIONS/INTERPRETATION: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.
- MeSH
- diabetes mellitus 2. typu epidemiologie genetika MeSH
- genetická predispozice k nemoci MeSH
- genetické testování MeSH
- hepatocytární jaderný faktor 1-alfa * genetika MeSH
- hepatocytární jaderný faktor 4 * genetika MeSH
- lidé MeSH
- mutace * MeSH
- prevalence MeSH
- protein-serin-threoninkinasy * MeSH
- rodokmen MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
- MeSH
- lidé MeSH
- nemoci jater diagnóza MeSH
- pletyzmografie impedanční metody MeSH
- Check Tag
- lidé MeSH
