Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects
Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects
复制标题
DOI：
10.1073/pnas.021544398
复制
发表时间：
2001-01-16
影响因子：
11.1
通讯作者：
Takeda, J
中科院分区：
文献类型：
--
作者：
Nishigori, H;Tomura, H;Takeda, J
编码肝细胞核因子 (HNF) 级联转录因子的多个基因的突变与青少年发病型糖尿病 (MODY) 相关，MODY 是早发性糖尿病的一种单基因形式。孤儿核受体小异二聚体伴侣（SHP，NR0B2）调节MODY1蛋白（核受体HNF-4α）转录活性的能力表明SHP作为候选MODY基因。我们对 173 名不相关的日本早发糖尿病受试者进行了该基因突变的筛查，发现 6 名受试者中有 5 种不同的突变（H53fsdel10、L98fsdel9insAC、R34X、A195S 和 R213C）以及一种明显的多态性（R216H），均以杂合状态存在。有趣的是，所有携带突变的受试者在糖尿病发作时都是轻度或中度肥胖，对这些个体的谱系分析表明，SHP 突变与肥胖相关，而不是与糖尿病相关。因此，另外一组 101 名不相关的非糖尿病早发性肥胖受试者接受了 SHP 基因突变筛查。在 6 名受试者中发现了两个先前观察到的突变（R34X 和 A195S）以及另外两个突变（R57W 和 G189E），而在 116 名年轻的非糖尿病瘦对照中没有发现突变（P = 0.0094）。突变蛋白的功能研究表明，突变导致 SHP 活性丧失。这些结果表明，SHP 基因的遗传变异导致体重增加，并揭示了导致日本人这种常见代谢紊乱的途径。
Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4 alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10. L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.