Novel melanocortin-3 and -4 receptor functional variants in Asian children with severe obesity.

This study aims to identify and functionally characterize Melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) variants in an Asian cohort of children with severe early-onset obesity. Whole exome sequencing was performed to screen for MC3R and MC4R coding variants in 488 Asian children with early-onset severe obesity (BMI for age ≥ 97th percentile). Functionality of the identified variants were determined via measurement of intracellular cyclic adenosine monophosphate (cAMP) concentrations and luciferase activity. Four MC3R and two MC4R heterozygous non-synonymous rare variants were detected. There were 3 novel variants: MC3R c.151G > C (p.Val51Leu), MC4R c.127C > A (p.Gln43Lys) and MC4R c.272T > G (p.Met91Arg), and 3 previously reported variants: MC3R c.127G > A (p.Glu43Lys), MC3R c.97G > A (p.Ala33Thr) and MC3R c.437T > A (p.Ile146Asn). Both MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants demonstrated defective downstream cAMP signaling activity. MC4R c.127C > A (p.Gln43Lys) variant showed reduced cAMP signaling activity at low substrate concentration but the signaling activity was restored at high substrate concentration. MC3R c.151G > C (p.Val51Leu) variant did not show a significant reduction in cAMP signaling activity compared to wild-type MC3R. Co-expression studies of the wild-type and variant MC3R/MC4R showed that the heterozygous variants did not exhibit dominant negative effect. Our functional assays demonstrated that MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants might be predisposing to early-onset obesity and further studies are needed to establish the causative effect of these variants in the pathogenesis of obesity.

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