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

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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.

Original languageEnglish
Article numbere1004124
JournalPLoS Genetics
Volume10
Issue number2
DOIs
Publication statusPublished - 13 Feb 2014

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Corpus Striatum
metabolic syndrome
dopamine
obesity
mutation
Dopamine
neurons
Neurons
Obesity
Mutation
gene
Endoplasmic Reticulum
endoplasmic reticulum
Genes
genes
Sequence Tagged Sites
family studies
Dopamine D1 Receptors
mutants
loci

Cite this

Zhang, Z., Hao, C-J., Li, C-G., Zang, D-J., Zhao, J., Li, X-N., ... Li, W. (2014). Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons. PLoS Genetics, 10(2), [e1004124]. https://doi.org/10.1371/journal.pgen.1004124

Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons. / Zhang, Zhe; Hao, Chan-Juan; Li, Chang-Gui; Zang, Dong-Jie; Zhao, Jing; Li, Xiao-Nan; Wei, Ai-Hua; Wei, Zong-Bo; Yang, Lin; He, Xin; Zhen, Xue-Chu; Gao, Xiang; Speakman, John R; Li, Wei.

In: PLoS Genetics, Vol. 10, No. 2, e1004124, 13.02.2014.

Research output: Contribution to journalArticle

Zhang, Z, Hao, C-J, Li, C-G, Zang, D-J, Zhao, J, Li, X-N, Wei, A-H, Wei, Z-B, Yang, L, He, X, Zhen, X-C, Gao, X, Speakman, JR & Li, W 2014, 'Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons', PLoS Genetics, vol. 10, no. 2, e1004124. https://doi.org/10.1371/journal.pgen.1004124
Zhang, Zhe ; Hao, Chan-Juan ; Li, Chang-Gui ; Zang, Dong-Jie ; Zhao, Jing ; Li, Xiao-Nan ; Wei, Ai-Hua ; Wei, Zong-Bo ; Yang, Lin ; He, Xin ; Zhen, Xue-Chu ; Gao, Xiang ; Speakman, John R ; Li, Wei. / Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons. In: PLoS Genetics. 2014 ; Vol. 10, No. 2.
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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.",
author = "Zhe Zhang and Chan-Juan Hao and Chang-Gui Li and Dong-Jie Zang and Jing Zhao and Xiao-Nan Li and Ai-Hua Wei and Zong-Bo Wei and Lin Yang and Xin He and Xue-Chu Zhen and Xiang Gao and Speakman, {John R} and Wei Li",
note = "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.",
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AU - Zhao, Jing

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AU - Wei, Ai-Hua

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N1 - 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.

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N2 - 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.

AB - 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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