英国剑桥大学Stephen O’Rahilly、布里斯托大学Nicholas J. Timpson等研究人员合作揭示黑皮质素4受体的功能丧失突变。该项研究成果于2021年5月27日在线发表在《自然—医学》杂志上。

研究人员检查了来自父母和儿童的雅芳纵向研究中 5,724 名参与者的黑皮质素 4 受体基因 (MC4R) 编码序列，对所有非同义 MC4R 变体进行了功能表征，并检查了它们与从童年到成年早期的人体测量表型的关联。MC4R 中杂合功能丧失 (LoF) 突变的频率为 337 分之一 (0.30%)，远高于之前的估计。

在 18 岁时，LoF 突变携带者和非携带者之间的体重、体重指数和脂肪量的平均差异分别为 17.76 kg（95% CI 9.41, 26.10）、4.84 kg m^-2（95% CI 2.19, 7.49）和 14.78 kg (95% CI 8.56, 20.99)。MC4R LoF突变可能比之前报道的更常见，并且此类变异的携带者可能会带着过度肥胖的沉重负担进入成年生活。

据了解，MC4R基因中的突变与肥胖有关，但人们对此类突变在人类生长和发育过程中的普遍性和影响知之甚少。

附：英文原文

Title: Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Author: Kaitlin H. Wade, Brian Y. H. Lam, Audrey Melvin, Warren Pan, Laura J. Corbin, David A. Hughes, Kara Rainbow, Jian-Hua Chen, Katie Duckett, Xiaoming Liu, Jacek Mokrosiski, Alexander Mrseburg, Sam Neaves, Alice Williamson, Chen Zhang, I. Sadaf Farooqi, Giles S. H. Yeo, Nicholas J. Timpson, Stephen ORahilly

Issue&Volume: 2021-05-27

Abstract: Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76kg (95% CI 9.41, 26.10), 4.84kgm2 (95% CI 2.19, 7.49) and 14.78kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

DOI: 10.1038/s41591-021-01349-y

Source: https://www.nature.com/articles/s41591-021-01349-y