Channelpedia

PubMed 24207120


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1 , Nav1.7 , Nav1.8 , Nav1.9 , TRP , TRPA , TRPA1



Title: Gain-of-function mutations in SCN11A cause familial episodic pain.

Authors: Xiang Yang Zhang, Jingmin Wen, Wei Yang, Cheng Wang, Luna Gao, Liang 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 Yu Liu

Journal, date & volume: Am. J. Hum. Genet., 2013 Nov 7 , 93, 957-66

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24207120


Abstract
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 Nav1.9 (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 Nav1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel's 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.