对 SCN9A 相关疼痛疾病患者的遗传学、电生理学和病理学研究

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY
Jun-Hui Yuan, Xiaoyang Cheng, Eiji Matsuura, Yujiro Higuchi, Masahiro Ando, Akihiro Hashiguchi, Akiko Yoshimura, Ryo Nakachi, Jun Mine, Takeshi Taketani, Kenichi Maeda, Saori Kawakami, Ryutaro Kira, Shoko Tanaka, Kazuaki Kanai, Fadia Dib-Hajj, Sulayman D. Dib-Hajj, Stephen G. Waxman, Hiroshi Takashima
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引用次数: 0

摘要

背景和目的 由 SCN9A 基因编码的电压门控钠通道 Nav1.7 与多种疼痛性周围神经病有关,其中以遗传性红斑性肢痛症(EM)和阵发性极度疼痛症(PEPD)为代表。本研究旨在确定神经病理性疼痛患者的遗传病因,并揭示其潜在的发病机制。 方法 我们招募了八名早发性疼痛性周围神经病患者,其中六名表现为 EM/EM 类疾病,两名临床诊断为 PEPD。我们对与遗传性感觉和/或自主神经病变相关的18个基因进行了基因组测序。我们将新型 SCN9A 突变(F1624S)导入 GFP-2A-Nav1.7rNS 质粒,然后将构建体瞬时转染到 HEK293 细胞中。我们使用自动高通量膜片钳系统鉴定了野生型和 F1624S Nav1.7 通道。 结果 我们从两名表现出 EM-like/EM 表型的患者中发现了两个 SCN9A 突变,即 I136V 和 P1308L。在两名被诊断为 PEPD 的患者中,我们发现了 SCN9A 的另外两个突变,即 F1624S(新型)和 A1632E。对 Nav1.7-F1624S 的贴片钳分析表明,稳态快速失活(17.4 mV,p < .001)和慢速失活(5.5 mV,p < .001)均有去极化偏移,但对通道激活没有影响。 解释 我们在患者身上观察到的临床特征拓宽了 SCN9A 相关疼痛疾病的表型谱,电生理分析丰富了对 Nav1.7 功能增益突变引起的基因型-表型关联的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders

Background and Aims

Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis.

Methods

We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system.

Results

From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed.

Interpretation

Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype–phenotype association caused by Nav1.7 gain-of-function mutations.

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来源期刊
CiteScore
6.10
自引率
7.90%
发文量
45
审稿时长
>12 weeks
期刊介绍: The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders. The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies. Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials. The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.
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