Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off
Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off
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DOI：
10.1016/j.expneurol.2008.12.012
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Choi, Jin-Sung;Zhang, Lili;Waxman, Stephen G.
遗传性红斑性肢痛症（IEM）以间歇性灼痛和四肢红斑为特征，是由钠通道Na(v)1.7的功能获得性突变引起的，Na(v)1.7优先表达于伤害性和交感神经元。大多数患者对药物治疗没有反应，尽管偶尔有报告表明患者使用利多卡因或美西汀可以部分缓解。一名7岁女孩，有两年的对称性灼痛和手脚红斑病史，被诊断为红斑性肢痛症。美西汀治疗减少了疼痛发作的次数和严重程度。我们在此报告了该患者的一个新的IEM Na(v)1.7突变及其对美西汀的反应。先证者的SCN9A外显子扩增并测序。我们在第15外显子发现了一个单核苷酸替代（T2616G），在200个种族匹配的对照等位基因中不存在，它在DII/S5中用甘氨酸（V872G）替代缬氨酸872。哺乳动物细胞中野生型和突变型Na(v)1.7通道的全细胞膜片钳分析表明，V872G使激活位移-10 mV，减慢失活速度，并产生更大的斜坡电流。我们观察到，与野生型通道相比，暴露于美西汀后，V872G电流的使用依赖性下降更强。这些观察结果表明，由于对突变体Nav1.7通道的使用依赖性作用，一些IEM患者可能对美西汀表现出良好的反应。即使在美西汀停用后，疼痛仍持续缓解，这可能表明早期治疗可以减缓疾病的进展。(c) 2008爱思唯尔公司版权所有。
Inherited erythromelalgia (IEM), characterized by episodic burning pain and erythema of the extremities, is produced by gain-of-function mutations in sodium channel Na(v)1.7, which is preferentially expressed in nociceptive and sympathetic neurons. Most patients do not respond to pharmacotherapy, although occasional reports document patients as showing partial relief with lidocaine or mexiletine. A 7-year-old girl, with a two-year history of symmetric burning pain and erythema in her hands and feet, was diagnosed with erythromelalgia. Treatment with mexiletine reduced the number and severity of pain episodes. We report here a new IEM Na(v)1.7 Mutation in this patient, and its response to mexiletine. SCN9A exons from the proband were amplified and sequenced. We identified a single nucleotide substitution (T2616G) in exon 15, not present in 200 ethnically-matched control alleles, which substitutes valine 872 by glycine (V872G) within DII/S5. Whole-cell patch-clamp analysis of wild-type and mutant Na(v)1.7 channels in mammalian cells show that V872G shifts activation by -10 mV, slows deactivation, and generates larger ramp currents. We observed a stronger use-dependent fall-off in Current following exposure to mexiletine for V872G compared to wild-type channels. These observations Suggest that some patients with IEM may show a favorable response to mexiletine due to a use-dependent effect on mutant Nav1.7 channels. Continued relief from pain, even after mexiletine was discontinued in this patient, might suggest that early treatment may slow the progression of the disease. (c) 2008 Elsevier Inc. All rights reserved.