2. Academic Validation
  3. Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons

Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons

  • PLoS Genet. 2014 Feb 13;10(2):e1004124. doi: 10.1371/journal.pgen.1004124.
Zhe Zhang 1,  Chan-Juan Hao 2,  Chang-Gui Li 3,  Dong-Jie Zang 4,  Jing Zhao 5,  Xiao-Nan Li 6,  Ai-Hua Wei 7,  Zong-Bo Wei 1,  Lin Yang 4,  Xin He 4,  Xue-Chu Zhen 8,  Xiang Gao 5,  John R Speakman 9,  Wei Li 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China ; Graduate School of Chinese Academy of Sciences, Beijing, China.
  • 2 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China ; Graduate School of Chinese Academy of Sciences, Beijing, China ; Reproductive and Genetic Center, National Research Institute for Family Planning, Beijing, China.
  • 3 The Affiliated Hospital of Qingdao University Medical College, Qingdao, China.
  • 4 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 5 Model Animal Research Center, Nanjing University, Nanjing, China.
  • 6 Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China.
  • 7 Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 8 Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, China.
  • 9 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China ; Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
PMID: 24550737 DOI: 10.1371/journal.pgen.1004124
Abstract

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.

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