Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Virchowstr, 171, D 45147, Essen, Germany.
BMC Med Genomics. 2012 Dec 27;5:65. doi: 10.1186/1755-8794-5-65.
The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.
We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.
We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3' end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.
The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.
SH2B1 基因（Src 同源 2B 衔接蛋白 1 基因）是肥胖的一个可靠候选基因。大规模全基因组关联研究描绘了基因附近的标记；动物模型表明，它可能与人类体重调节有关。
我们对 95 名极度肥胖的儿童和青少年的 SH2B1 编码序列中的变体进行了突变筛选。在独立的儿童和成人研究组（最多 11406 名肥胖或超重个体和 4568 名对照）中对检测到的变体进行了基因分型。在体外分析了检测到的变体对 STAT3 介导的瘦素信号的功能影响。
我们在 SH2B1 中发现了两个新的罕见突变和五个已知的单核苷酸多态性（rs147094247、rs7498665、rs60604881、rs62037368 和 rs62037369）。突变 g.9483C/T 导致 SH2B1 的 β（βThr656Ile）和 γ（γPro674Ser）剪接变体中的非同义、非保守性交换。它还在 11206 名（极度）肥胖或超重的儿童、青少年和成年人中的 2 名中被检测到，但在 4506 名基于人群的正常体重或瘦对照中未被检测到。SH2B1 3' 端的非编码突变 g.10182C/A 仅在 3 名肥胖个体中被检测到。对于非同义 SNP rs7498665（Thr484Ala），我们在 705 个肥胖三联体中观察到先前描述的风险等位基因的名义过度传递（名义 p=0.009，OR=1.23），并且在 359 例病例中相同等位基因的频率增加与 429 名对照相比（名义 p=0.042，OR=1.23）。Thr484Ala 和 βThr656Ile/γPro674Ser 处的肥胖风险等位基因对剪接变体 β 和 γ 中的瘦素受体信号没有影响。
SH2B1 中的罕见编码突变βThr656Ile/γPro674Ser（g.9483C/T）仅在超重或肥胖个体中被检测到。功能分析未发现突变 SH2B1 中瘦素信号受损。
