Elucidating the genetic basis of severe obesity: learning from the experiments of nature

Abstract

We investigate the role of three candidate genes in the pathogenesis of childhood obesity: pro-opiomelanocortin gene (POMC), melanocortin-4 receptor gene (MC4R), and melanocortin-3 receptor gene (MC3R). More than 200 severely obese local children with percentage weight for height >150% were recruited to our Obesity Gene Study (OGS). MC3R and MC4R genes of this cohort were screened. Three novel heterozygous MC3R mutations (Ile183Asn, Ala70Thr, and Met134Ile) were identified in three unrelated subjects (OGS). Three MC4R mutations (c.631-634delCTCT, Tyr157Ser, and c.976delT) were identified in three subjects (OGS). In a separate study, the POMC gene of more than 900 DNA samples from the Genetics of Obesity Study (GOOS) (Cambridge, UK) was examined. Five probands (GOOS) were heterozygous for a rare missense variant of POMC in the region encoding N2-MSH, Tyr221Cys, as well as two heterozygous missense POMC mutations, Cys28Phe and Leu37Phe. Through family genetic studies and in-vitro studies, we demonstrated that the MC4R mutations resulted in an autosomal codominant form of obesity with variable expressivity, and heterozygous MC3R and POMC mutations did not result in autosomal dominant forms of obesity, but may contribute as predisposing factors to early-onset obesity, and exert an effect on the human phenotype.