Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy
Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy
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DOI：
10.1002/ana.22485
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发表时间：
2012-01-01
影响因子：
11.2
通讯作者：
Merkies, Ingemar S. J.
中科院分区：
文献类型：
--
作者：
Faber, Catharina G.;Hoeijmakers, Janneke G. J.;Merkies, Ingemar S. J.
目的：小神经纤维神经病（SFN）的发生往往没有明显的原因，但没有系统的遗传学研究已在特发性SFN（I-SFN）患者进行。我们试图通过对活检证实的特发性SFN患者进行SCN 9A基因突变筛查来确定I-SFN的遗传基础，SCN 9A基因编码电压门控钠通道NaV1.7，优先在小直径外周轴突中表达。研究方法：对符合类似于2种SFN相关症状、正常力量、腱反射、振动感觉和神经传导研究、表皮内神经纤维密度降低（IENFD）加上定量感觉测试（QST）异常以及无SFN潜在病因的标准的可能I-SFN患者进行临床评估，并通过筛查SCN 9A突变和功能分析进行评估。结果：28例符合I-SFN严格标准的患者，包括异常IENFD和QST，进行了SCN 9A基因分析。在这28例经活检证实的I-SFN患者中，发现8例在SCN 9A中携带新突变。功能分析显示，突变通道的功能变化的多个增益;每个突变使背根神经节神经元过度兴奋。释义：我们首次发现，钠通道NaV1.7的功能突变，使背根神经节神经元过度兴奋，是目前在一个相当大的比例（28.6%; 8 28）的患者符合严格的标准I-SFN的增益。这些结果表明，NaV1.7突变在神经系统疾病中的作用比以前认为的罕见遗传综合征的研究更广泛，并提出了I-SFN的病因学基础，即小直径外周轴突中功能获得突变钠通道的表达可能导致这些纤维变性。神经网络2012; 71：26-39
Objective: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel NaV1.7, which is preferentially expressed in small diameter peripheral axons. Methods: Patients referred with possible I-SFN, who met the criteria of similar to 2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. Results: Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. Interpretation: We show for the first time that gain of function mutations in sodium channel NaV1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of NaV1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate. ANN NEUROL 2012; 71: 26-39