Mutation of SLC35D3 Causes Metabolic Syndrome by Impairing Dopamine Signaling in Striatal D1 Neurons

Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS). A locus near a sequence tagged site (STS) marker D6S1009 has been linked to obesity or body mass index (BMI). However, its genetic entity is unknown. D6S1009 is located in the intergenic region between SLC35D3 and NHEG1. Here we report that the ros mutant mice harboring a recessive mutation in the Slc35d3 gene show obesity and MetS and reduced membrane dopamine receptor D1 (D1R) with impaired dopamine signaling in striatal neurons. SLC35D3 is localized to both endoplasmic reticulum (ER) and early endosomes and interacts with D1R. In ros striatal D1 neurons, lack of SLC35D3 causes the accumulation of D1R on the ER to impair its ER exit. The MetS phenotype is reversible by the administration of D1R agonist to the ros mutant. In addition, we identified two mutations in the SLC35D3 gene in patients with MetS, which alter the subcellular localization of SLC35D3. Our results suggest that the SLC35D3 gene, close to the D6S1009 locus, is a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling.肥胖是当今全球面临的最重大公共健康问题之一。尽管双生子及家系研究显示，约三分之二的肥胖病例由遗传因素导致，但目前仅阐明了其中极小一部分遗传变异。仍有大量与体脂含量变异及代谢综合征（metabolic syndrome, MetS）所涵盖的相关疾病相关的基因有待发掘。此前有研究发现，位于序列标签位点（sequence tagged site, STS）标记D6S1009附近的基因座与肥胖或体重指数（body mass index, BMI）存在关联，但其具体遗传本质仍未明确。D6S1009坐落于SLC35D3与NHEG1之间的基因间区。本研究发现，Slc35d3基因携带隐性突变的ros突变小鼠会表现出肥胖与代谢综合征表型，其纹状体神经元细胞膜上的多巴胺受体D1（dopamine receptor D1, D1R）表达水平下调，且多巴胺信号传导功能受损。SLC35D3同时定位于内质网（endoplasmic reticulum, ER）与早期内涵体，并可与D1R发生相互作用。在ros突变小鼠的纹状体D1神经元中，SLC35D3的缺失会导致D1R在内质网上异常蓄积，进而阻碍其从内质网的转运输出。向ros突变小鼠施用D1R激动剂可逆转其代谢综合征表型。此外，我们在代谢综合征患者体内鉴定出SLC35D3基因的两个突变位点，这些突变会改变SLC35D3的亚细胞定位。本研究结果表明，紧邻D6S1009基因座的SLC35D3基因是代谢综合征的候选致病基因，其通过调控多巴胺信号传导参与中枢神经系统的代谢调控。