肥胖症基因SLC35D3的功能和遗传学研究

Obesity, together with its associated disorders, is one of the largest health problems facing the world today. Obesity is caused by the interaction between environmental and genetic factors. Although about two-third of the variance in obesity population is explained by genetic factors, only a small fraction of this variance has been unraveled. We recently reported that SLC35D3 gene is a novel candidate gene for obesity. Mutation of SLC35D3 causes the reduction of membrane D1 dopamine receptor (D1R) and impaired dopamine signaling in the striatal neurons. Our preliminary data showed that SLC35D3 interacted with DRiP78, another protein involved in D1R membrane trafficking. In this proposal, we aim to study the molecular and cellular mechanism of D1R membrane trafficking mediated by the interaction between SLC35D3 and DRiP78. On the other hand, we plan to screen mutations of SLC35D3 gene in 1000 obesity people to determine the mutational frequency, pathological effects of novel mutational alleles, and the structure-functional relationship of the SLC35D3 gene. This will be significant for the translational studies in Chinese obesity population.

肥胖症的发生率逐年上升,且易导致多种代谢异常并发症的发生，严重威胁着人类的健康。肥胖症的发生一般认为是遗传与环境的相互作用所引起，其中遗传因素的贡献约占2/3，但其中绝大多数基因位点的遗传病理机制尚不明确。我们最近报道了SLC35D3基因是肥胖症的新致病基因，其表达产物参与多巴胺I型受体(D1R)由内质网到质膜的转运，但其具体机制尚有待阐明。初步研究发现SLC35D3与另一调节D1R膜运输的DRiP78蛋白有直接相互作用。本项目拟探讨DRiP78和SLC35D3两者共同参与D1R膜运输的分子细胞机制；同时在超过1000例的大样本肥胖症患者群体中筛查SLC35D3基因的突变，鉴定新发现SLC35D3突变等位基因对D1R膜运输的影响，以明确该基因突变在中国肥胖人群的发生率、突变等位基因的病理效应及SLC35D3结构与功能的关系。此项研究对于肥胖症基因SLC35D3的转化应用具有重要意义。