Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain
Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain
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SCN11A 的功能获得突变导致家族性阵发性疼痛
DOI：
10.1016/j.ajhg.2013.09.016
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发表时间：
2013-11-07
影响因子：
9.8
通讯作者：
Liu, Jing Yu
中科院分区：
文献类型：
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作者：
Zhang, Xiang Yang;Wen, Jingmin;Liu, Jing Yu
许多离子通道基因与人类遗传性疼痛障碍有关。在这里，我们报告两个大的中国家庭与常染色体显性发作性疼痛。在排除了导致与我们的发现相似的疼痛综合征的三个已知基因（SCN 9A，SCN 10A和TRPA 1）的突变后，我们用微卫星标记进行了全基因组连锁扫描，并将遗传位点定位在染色体3p22.3-p21.32上的7.81 Mb区域。通过使用全外显子组测序和常规的桑格测序，我们在编码电压门控钠通道Na（v）1.9（SCN 11 A）的基因中鉴定了两个错义突变：c.673C>T（p.Arg225Cys）和c.2423C>G（p.Ala808Gly）（每个家族一个）。每个突变与相应家族中的疼痛表型表现出完美的共分离，并且在1，021名正常个体中均未检测到。这两个错义突变被预测为改变人Na（v）1.9通道的高度保守的氨基酸残基。我们在小鼠背根神经节（DRG）神经元中表达了两个SCN 11 A突变体，结果表明这两个突变体都增强了通道的电活动，并诱导了DRG神经元的过度兴奋。总之，我们的研究结果表明，SCN 11 A的功能获得性突变可能是常染色体显性发作性疼痛障碍的原因。
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(v)1.9 (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(v)1.9 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.