We thank Dr. Ya-Qin Feng from Shanxi Medical University, Dr. Tian-Yun Gao from Nanjing University and Dr. Yan-Hong Xue from Institute of Biophysics (CAS) for technical assistance in this study. We are very thankful to Drs. Richard T. Swank and Xiao-Jiang Li for their critical reading of this manuscript and invaluable advice. Funding: This work was partially supported by grants from National Basic Research Program of China (2013CB530605; 2014CB942803), from National Natural Science Foundation of China 1230046; 31071252; 81101182) and from Chinese Academy of Sciences (KSCX2-EW-R-05, KJZD-EW-L08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Gao, Xiang

Hao, Chan-Juan

He, Xin

Li, Chang-Gui

Li, Wei

Li, Xiao-Nan

Speakman, John R

Wei, Ai-Hua

Wei, Zong-Bo

Yang, Lin

Zang, Dong-Jie

Zhang, Zhe

Zhao, Jing

Zhen, Xue-Chu

PLoS Genetics

English

PubMed

<div>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.</div

Zhe Zhang (81603)

Chan-Juan Hao (58406)

Chang-Gui Li (386380)

Dong-Jie Zang (523079)

Jing Zhao (21160)

Xiao-Nan Li (220248)

Ai-Hua Wei (523080)

Zong-Bo Wei (523081)

Lin Yang (45852)

Xin He (48101)

Xue-Chu Zhen (292935)

Xiang Gao (4077)

John R. Speakman (380055)

Wei Li (7081)

The Francis Crick Institute

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

Zhe Zhang

Chan-Juan Hao

Chang-Gui Li

Dong-Jie Zang

Jing Zhao

Xiao-Nan Li

Ai-Hua Wei

Zong-Bo Wei

Lin Yang

Xin He

Xue-Chu Zhen

Xiang Gao

John R. Speakman

Wei Li

Crossref

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

John R Speakman

Directory of Open Access Journals

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

We thank Dr. Ya-Qin Feng from Shanxi Medical University, Dr. Tian-Yun Gao from Nanjing University and Dr. Yan-Hong Xue from Institute of Biophysics (CAS) for technical assistance in this study. We are very thankful to Drs. Richard T. Swank and Xiao-Jiang Li for their critical reading of this manuscript and invaluable advice. Funding: This work was partially supported by grants from National Basic Research Program of China (2013CB530605; 2014CB942803), from National Natural Science Foundation of China 1230046; 31071252; 81101182) and from Chinese Academy of Sciences (KSCX2-EW-R-05, KJZD-EW-L08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

The Open University

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

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

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Directory of Open Access Journals

The Open University