Melanocortin-4-receptor molecular screening in a group of phenotipically selected obese children: report of two new mutations and lack of association to the early onset of the disease

Background: Melanocortin-4-receptor (MC4R) mutations represent the most frequent geneticcause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show aparticular phenotype characterized by early onset, severe obesity and high stature. To verifywhether MC4R mutations are associated with this particular phenotype in the Italian pediatricpopulation, we decided to screen the MC4R gene in a group of obese children selected on the basisof their phenotype.Methods: to perform this study, a multicentric approach was designed. Particularly, to be enrolledin the study subjects needed to meet the following criteria: Body mass index ≥ 3 deviation scoresaccording to age and sex, familiar history of obesity (at least one parent obese), obesity onset beforethe 10 years old, height ≥ 2 deviation scores. The coding region of MC4R gene was screened in 240obese children (mean age 8.3±3.1, mean BMI 30.8 ± 5.4) and in 200 controls (mean age 8.1± 2.8;mean BMI 14.2 ± 2.5).Results: three mutations have been found in five obese children. The S127L (C380T), found inthree unrelated children, had been described and functionally characterized previously. The Q307X(C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showedthat only Q307X impaired protein function.Conclusions: the low prevalence of MC4R mutations (1.6%) in this group of obese childrenselected according to the obesity degree, the tall stature and the family history of obesity wassimilar to the prevalence observed in previous screenings performed in obese adults and in notphenotypically selected obese children.