Background: Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity.

Aims: 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 (BMI) of MC4R mutation carriers with non-carriers in longitudinal studies, 4) to determine the effect of a weight management 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, BMI, baseline biochemical data and a weight loss follow-up study were 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 non-carriers during 13 years of follow-up did not reveal any significant differences. MC4R mutation carriers exhibited a similar ability to lose weight as obese non-carriers. The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R.

Conclusions: Among Czech obese 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 non-carriers.