Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain

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• 作者：Xiang聽Yang Zhang ; Jingmin Wen ; Wei Yang ; Cheng Wang ; Luna Gao ; Liang聽Hong Zheng ; Tao Wang ; Kaikai Ran ; Yulei Li ; Xiangyang Li ; Ming Xu ; Junyu Luo ; Shenglei Feng ; Xixiang Ma ; Hongying Ma ; Zuying Chai ; Zhuan Zhou ; Jing Yao ; Xue Zhang ; Jing聽Yu Liu ; et al.
• 刊名：The American Journal of Human Genetics
• 出版年：7 November, 2013
• 年：2013
• 卷：93
• 期：5
• 页码：957-966
• 全文大小：2169 K

文摘

Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.81 Mb region on chromosome 3p22.3-p21.32. By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Na_v1.9 (SCN11A): c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1,021 normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Na_v1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel鈥檚 electrical activities and induced hyperexcitablity of DRG neurons. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder.