Identification and functional analysis of novel human melanocortin-4 receptor variants

Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting resul ts in mice that develop maturity-onset obesity, hyperinsulinemia, and hyper glycemia. These phenotypes resemble common forms of human obesity, which ar e late-onset and frequently accompanied by NIDDM. It is not clear whether s equence variation of the MC4-R gene contributes to obesity in humans. There fore, we examined the human MC4-R gene polymorphism in 190 individuals asce rtained on obesity status. Three allelic variants mere identified, includin g two novel ones, Thr(112)Met and Ile(137)Thr. To analyze possible function al alterations, the variants mere cloned and expressed in vitro and compare d with the wild-type receptor. One of the novel variants, Ile(137)Thr, iden tified in an extremely obese proband (BMI 57), was found to be severely imp aired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.