Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
International Laboratory for Human Genome Research, National Autonomous University of Mexico, Campus Juriquilla, Queretaro, Mexico.
Obesity (Silver Spring). 2024 Sep;32(9):1769-1777. doi: 10.1002/oby.24101.
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.
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.
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.
In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.
在多基因肥胖流行的人群中，可能会遗漏某些单基因肥胖病例，而这些病例可能对特定的治疗方法有反应。本研究通过对 6803 名纵向研究个体的外显子组全序列数据，在一个群体中研究了已确立的单基因肥胖基因中的罕见 DNA 变异。
分析了 15 个单基因肥胖基因的外显子数据，以观察到任何 BMI z 分数最大值>2 的儿童（n=279）中存在而非 BMI z 分数最大值≤0 的儿童（n=1542）或 BMI 处于前 5%的成人中存在的非 synonymous变异（n=263），但在 BMI 中位数以下的成人中不存在（n=2629）。然后使用荧光素酶检测对变体进行功能分析。
肥胖病例与对照之间的比较确定了六个基因中的八个错义变体：DYRK1B、KSR2、MC4R、NTRK2、PCSK1 和 SIM1。其中，MC4R p.A303P 和 p.R165G 先前已被证明会损害 MC4R 功能。对其余六个变体的功能分析表明，KSR2 p.I402F 和 p.T193I 和 NTRK2 p.S249Y 改变了蛋白质功能。
除 MC4R 外，KSR2 和 NTRK2 中的罕见错义变异也可能解释了携带者中观察到的严重肥胖。
