Ong Siong Gim, Dehghan Roghayeh, Dorajoo Rajkumar, Liu Jian-Jun, Sng Andrew Anjian, Lee Yung Seng, Ooi Delicia Shu Qin
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Division of Paediatric Endocrinology, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore 119228, Singapore.
J Clin Endocrinol Metab. 2024 Feb 20;109(3):e1249-e1259. doi: 10.1210/clinem/dgad602.
Genetic variants in melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) genes are strongly associated with childhood obesity.
This study aims to identify and functionally characterize MC3R and 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 severe early-onset obesity (body mass index 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 2 MC4R heterozygous nonsynonymous 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. The 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. The MC3R c.151G > C (p.Val51Leu) variant did not show a significant reduction in cAMP signaling activity compared to wild-type (WT) MC3R. Coexpression studies of the WT 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 predispose individuals to early-onset obesity, and further studies are needed to establish the causative effect of these variants in the pathogenesis of obesity.
黑皮质素3受体（MC3R）和黑皮质素4受体（MC4R）基因中的遗传变异与儿童肥胖密切相关。
本研究旨在鉴定一组亚洲重度早发性肥胖儿童中的MC3R和MC4R变异，并对其进行功能表征。
对488名亚洲重度早发性肥胖儿童（年龄别体重指数≥第97百分位数）进行全外显子测序，以筛选MC3R和MC4R编码变异。通过测量细胞内环磷酸腺苷（cAMP）浓度和荧光素酶活性来确定所鉴定变异的功能。
检测到4个MC3R杂合非同义罕见变异和2个MC4R杂合非同义罕见变异。有3个新变异：MC3R c.151G > C（p.Val51Leu）、MC4R c.127C > A（p.Gln43Lys）和MC4R c.272T > G（p.Met91Arg），以及3个先前报道的变异：MC3R c.127G > A（p.Glu43Lys）、MC3R c.97G > A（p.Ala33Thr）和MC3R c.437T > A（p.Ile146Asn）。MC3R c.127G > A（p.Glu43Lys）和MC4R c.272T > G（p.Met91Arg）变异均表现出下游cAMP信号传导活性缺陷。MC4R c.127C > A（p.Gln43Lys）变异在低底物浓度下cAMP信号传导活性降低，但在高底物浓度下信号传导活性恢复。与野生型（WT）MC3R相比，MC3R c.151G > C（p.Val51Leu）变异的cAMP信号传导活性未显著降低。WT和变异型MC3R/MC4R的共表达研究表明，杂合变异未表现出显性负效应。
我们的功能分析表明，MC3R c.127G > A（p.Glu43Lys）和MC4R c.272T > G（p.Met91Arg）变异可能使个体易患早发性肥胖，需要进一步研究以确定这些变异在肥胖发病机制中的因果作用。
