Wu B, Zhang Y, Tang H, Yang M, Long H, Shi G, Tang J, Shi X
Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Curr Mol Med. 2017;17(6):450-457. doi: 10.2174/1566524017666171009105029.
Primary erythromelalgia (PE) is a dominant inherited disorder characterized by recurrent pain, redness, and warmth of the extremities that is caused by gain-of-function mutations in Nav1.7 encoding gene SCN9A. Most of the PE-causing mutations of Nav1.7 have been shown to be able to render Nav1.7-expressing cells hyperexcitable, however in most PE cases the symptoms are refractory to treatment with sodium channel blockers and the mechanism underlying the intractability has not been clearly clarified.
To identify the mutation of SCN9A in a Chinese Han family with typical symptoms of PE and study the electrophysiological effect of the identified mutation.
A Chinese Han family with typical symptoms of PE was collected and the proband's response to treatment was recorded. All the exons and flanking intronic sequences of SCN9A were amplified with PCR and sequenced. Several online programs were used to predict the damaging effect of variants. The functional effect of variants was studied by voltage-clamp analysis in CHO-K1 cells.
The PE symptoms of the proband are refractory to all kinds of reported medications. Sequence analysis of SCN9A showed that a novel c.2477T>A (p. F826Y) mutation co-segregated with the disease phenotype. Several online programs predicted that the F826Y mutation has a deleterious effect on the gene product. Voltage-clamp analysis showed that while compared with the wild-type channel, activation of the F826Y mutant channel was shifted by 7.7 mV in a hyperpolarizing direction, whereas steadystate inactivation was shifted by 4.3 mV in a depolarizing direction.
A novel disease-causing SCN9A Mutation (F826Y) was identified in a Chinese family with typical PE symptoms refractory to treatment. F826Y of Nav1.7 could render DRG neurons hyperexcitable, contributing to the pathogenesis of PE.
原发性红斑性肢痛症(PE)是一种显性遗传性疾病,其特征为四肢反复出现疼痛、发红和发热,由编码Nav1.7的基因SCN9A功能获得性突变引起。大多数导致PE的Nav1.7突变已被证明能够使表达Nav1.7的细胞过度兴奋,然而在大多数PE病例中,症状对钠通道阻滞剂治疗无效,其难治性的潜在机制尚未明确阐明。
鉴定一个具有典型PE症状的中国汉族家系中SCN9A的突变,并研究所鉴定突变的电生理效应。
收集一个具有典型PE症状的中国汉族家系,并记录先证者的治疗反应。用聚合酶链反应(PCR)扩增SCN9A的所有外显子和侧翼内含子序列并进行测序。使用几个在线程序预测变异的有害效应。通过在CHO-K1细胞中进行电压钳分析研究变异的功能效应。
先证者的PE症状对所有已报道的药物均无反应。SCN9A的序列分析显示,一个新的c.2477T>A(p.F826Y)突变与疾病表型共分离。几个在线程序预测F826Y突变对基因产物有有害影响。电压钳分析表明,与野生型通道相比,F826Y突变通道的激活在超极化方向上偏移了7.7 mV,而稳态失活在去极化方向上偏移了4.3 mV。
在一个具有典型且难治性PE症状的中国家系中鉴定出一种新的致病SCN9A突变(F826Y)。Nav1.7的F826Y可使背根神经节神经元过度兴奋,促成PE的发病机制。