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.
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SLC35D3 突变通过损害纹状体 D1 神经元中的多巴胺信号传导导致代谢综合征
DOI：
10.1371/journal.pgen.1004124
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Zhang Z;Hao CJ;Li CG;Zang DJ;Zhao J;Li XN;Wei AH;Wei ZB;Yang L;He X;Zhen XC;Gao X;Speakman JR;Li W
肥胖是当今世界面临的最大健康问题之一。尽管双胞胎和家庭研究表明，大约三分之二的肥胖是由遗传因素引起的，但这种差异中只有一小部分得到了解释。仍有大量基因有待鉴定，这些基因会导致身体肥胖的变化以及代谢综合征（MetS）中包含的相关疾病。序列标记位点（STS）标记D6S1009附近的一个位点与肥胖或体重指数（BMI）有关。然而，其遗传实体是未知的。D6S1009位于SLC35D3和NHEG1之间的基因间区。在这里，我们报道了Slc35d3基因隐性突变的ros突变小鼠表现出肥胖和MetS，膜多巴胺受体D1 （D1R）减少，纹状体神经元多巴胺信号通路受损。SLC35D3定位于内质网（ER）和早期内体，并与D1R相互作用。在逆纹状体D1神经元中，缺乏SLC35D3会导致D1R在内质网上的积累，从而损害其内质网的出口。通过对ros突变体施用D1R激动剂，MetS表型是可逆的。此外，我们在met患者中发现了SLC35D3基因的两个突变，它们改变了SLC35D3的亚细胞定位。我们的研究结果表明，靠近D6S1009位点的SLC35D3基因是MetS的候选基因，它通过调节多巴胺信号参与中枢神经系统的代谢控制。
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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影响因子：
6.7
作者：
Drong AW;Lindgren CM;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
4.5
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
Arya R;Lehman D;Hunt KJ;Schneider J;Almasy L;Blangero J;Stern MP;Duggirala R;Framingham Heart Study
通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
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