Identification and functional validation of rare coding variants in genes linked to monogenic obesity

IF 4.2 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Obesity Pub Date : 2024-08-28 DOI:10.1002/oby.24101

Çiğdem Köroğlu, Michael Traurig, Yunhua L. Muller, Samantha E. Day, Paolo Piaggi, Kim Wiedrich, Laura Vazquez, Robert L. Hanson, Cristopher V. Van Hout, Anna Alkelai, Alan R. Shuldiner, Clifton Bogardus, Leslie J. Baier

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Abstract

Objective

Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals.

Methods

Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays.

Results

The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function.

Conclusions

In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.

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单基因肥胖症相关基因中罕见编码变异的鉴定和功能验证。

目的：在多基因肥胖症盛行的人群中，罕见的单基因肥胖症病例可能无法被发现，而这些病例可能对特定的治疗方法有反应。本研究利用 6803 名纵向研究个体的全外显子组序列数据，研究了一个社区中已确定的单基因肥胖基因的罕见 DNA 变异：方法：分析了 15 个单基因肥胖基因的外显子组数据，以确定在最大 BMI z 得分大于 2 的儿童中观察到的非同义变异（N = 279），但在最大 BMI z 得分小于 0 的儿童中未观察到（N = 1542），或在 BMI 前 5 百分位数的成人中出现的非同义变异（N = 263），但在 BMI 中位数以下的成人中未出现（N = 2629）。然后使用荧光素酶测定法对变异进行功能分析：结果：肥胖症病例与对照组的比较发现了六个基因中的八个错义变异：结果：在肥胖病例和对照组的比较中发现了六个基因中的八个错义变异：DYRK1B、KSR2、MC4R、NTRK2、PCSK1 和 SIM1。其中，MC4R p.A303P 和 p.R165G 以前曾被证明会损害 MC4R 的功能。对其余六个变体的功能分析表明，KSR2 p.I402F和p.T193I以及NTRK2 p.S249Y会改变蛋白质的功能：结论：除 MC4R 外，KSR2 和 NTRK2 中的罕见错义变异也可能是导致携带者严重肥胖的潜在原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Obesity 医学-内分泌学与代谢

CiteScore

11.70

自引率

1.40%

发文量

261

审稿时长

2-4 weeks

期刊介绍： Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.