Identification and functional analysis of novel human melanocortin-4 receptor variants
Identification and functional analysis of novel human melanocortin-4 receptor variants
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DOI：
10.2337/diabetes.48.3.635
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发表时间：
1999-03-01
期刊：
影响因子：
7.7
通讯作者：
Allison, DB
中科院分区：
文献类型：
--
作者：
Gu, W;Tu, ZM;Allison, DB
通过基因靶向使黑皮质素-4受体（MC 4-R）失活导致小鼠发生成熟型肥胖、高胰岛素血症和高血糖症。这些表型类似于人类肥胖的常见形式，其是晚发性的并且经常伴有NIDDM。目前尚不清楚MC 4-R基因的序列变异是否会导致人类肥胖。因此，我们研究了人类MC 4-R基因多态性在190个人确定的肥胖状态。共鉴定出3个等位基因变异体，包括2个新的等位基因，Thr（112）Met和Ile（137）Thr。为了分析可能的功能改变，仅克隆变体并在体外表达，并与野生型受体进行比较。在一名极度肥胖的先证者（BMI 57）中发现的一种新变体Ile（137）Thr被发现在配体结合和信号传导方面严重受损，这增加了它可能有助于肥胖发展的可能性。此外，我们的研究结果还表明，MC 4-R编码区的序列多态性不太可能是研究人群中肥胖的常见原因，因为功能显著突变的频率较低。
Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting results in mice that develop maturity-onset obesity, hyperinsulinemia, and hyperglycemia. These phenotypes resemble common forms of human obesity, which are late-onset and frequently accompanied by NIDDM. It is not clear whether sequence variation of the MC4-R gene contributes to obesity in humans. Therefore, we examined the human MC4-R gene polymorphism in 190 individuals ascertained on obesity status. Three allelic variants mere identified, including two novel ones, Thr(112)Met and Ile(137)Thr. To analyze possible functional alterations, the variants mere cloned and expressed in vitro and compared with the wild-type receptor. One of the novel variants, Ile(137)Thr, identified in an extremely obese proband (BMI 57), was found to be severely impaired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.