Brief Genetics Report Co-occurrence of Two Partially Inactivating Polymorphisms of MC3R Is Associated With

Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2 % were double homozygous for a pair of missense MC3R se-quence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percent-age fat mass: P < 0.001), and had greater plasma leptin (P< 0.0001) and insulin concentrations (P< 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian chil-dren. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduc-tion, and less protein expression. We conclude that diminished MC3R expression in this double MC3R vari-ant may be a predisposing factor for excessive body weight gain in children. Diabetes 54:2663–2667, 2005 Both human linkage studies and knockout mousemodels suggest that MC3R (the melanocortin 3receptor gene) plays an important role in energyhomeostasis (1–5). Mice in whom both alleles of the MC3R have been inactivated have greater fat mass and reduced lean mass, while heterozygotes have normal body composition (3). Three human coding sequence variants have been reported in the MC3R (6–10): a heterozygous missense sequence variant Ile183Asn (I183N) that inacti-vates MC3R function (11,12), identified in two individuals (10), and two other variants, Thr6Lys and Val81Ile, that individually do not affect signal transduction (12) and have been reported not to be associated with body weight (6–9). Because most single gene mutations affecting body weight become manifest during childhood, we performed an MC3R mutation screening and association analysis in a large cohort of African-American and Caucasian over-weight and normal weight children and then performed functional studies for the sequence variants that were identified