Sporadic onset of erythermalgia:: A gain-of-function mutation in Nav1.7
Sporadic onset of erythermalgia:: A gain-of-function mutation in Nav1.7
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DOI：
10.1002/ana.20776
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发表时间：
2006-03-01
影响因子：
11.2
通讯作者：
Waxman, SG
中科院分区：
文献类型：
--
作者：
Han, CY;Rush, AM;Waxman, SG
目的：遗传性红斑痛症（红肢痛症）是一种常染色体显性遗传病，患者在轻度热刺激和运动后会出现四肢剧烈灼痛。虽然钠通道Na(v)1.7的突变已被证明是几个多代家族红斑痛症的基础，但散发性红斑痛症的分子基础仍是谜。我们研究了Na(v)1.7在一个中国家庭散发性红斑痛病例中的作用。方法对患者及其无症状家庭成员的基因组DNA进行测序，鉴定Na(v)1.7突变。采用全细胞膜片钳分析方法对野生型和突变型Na(v)1.7通道在哺乳动物细胞中的生物物理特性进行了表征。结果：在两名父母无症状的儿童中，Na(v)1.7的DIIS4-S5连接体存在单个氨基酸取代。无症状的父亲是基因突变的嵌合体。这种突变在通道激活中产生超极化位移，并且对缓慢、小的去极化的响应幅度增加。解释：Na(v)1.7基因的始创突变可以使周围感觉神经元亢奋，这可能是散发性红斑性痛症的基础。
Objective: Inherited erythermalgia (erythromelalgia) is an autosomal dominant disorder in which patients experience severe burning pain in the extremities, in response to mild thermal stimuli and exercise. Although mutations in sodium channel Na(v)1.7 have been shown to underlie erythermalgia in several multigeneration families with the disease that have been investigated to date, the molecular basis of erythermalgia in sporadic cases is enigmatic. We investigated the role of Na(v)1.7 in a sporadic case of erythermalgia in a Chinese family. Methods Genomic DNA from patients and their asymptomatic family members were sequenced to identify mutations in Na(v)1.7. Whole-cell patch clamp analysis was used to characterize biophysical properties of wild-type and mutant Na(v)1.7 channels in mammalian cells. Results: A single amino acid substitution in the DIIS4-S5 linker of Na(v)1.7 was present in two children whose parents were asymptomatic. The asymptomatic father was genetically mosaic for the mutation. This mutation produces a hyperpolarizing shift in channel activation and an increase in amplitude of the response to slow, small depolarizations. Interpretation: Founder mutations in Na(v)1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia.