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
{"title":"对 SCN9A 相关疼痛疾病患者的遗传学、电生理学和病理学研究","authors":"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","doi":"10.1111/jns.12590","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and Aims</h3>\n \n <p>Voltage-gated sodium channel Nav1.7, encoded by the <i>SCN9A</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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 <i>SCN9A</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>From two patients displaying EM-like/EM phenotypes, we identified two <i>SCN9A</i> mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in <i>SCN9A</i>, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, <i>p</i> < .001) and slow inactivation (5.5 mV, <i>p</i> < .001), but no effect on channel activation was observed.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Clinical features observed in our patients broaden the phenotypic spectrum of <i>SCN9A</i>-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype–phenotype association caused by Nav1.7 gain-of-function mutations.</p>\n </section>\n </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"597-607"},"PeriodicalIF":3.9000,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders\",\"authors\":\"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\",\"doi\":\"10.1111/jns.12590\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background and Aims</h3>\\n \\n <p>Voltage-gated sodium channel Nav1.7, encoded by the <i>SCN9A</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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 <i>SCN9A</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>From two patients displaying EM-like/EM phenotypes, we identified two <i>SCN9A</i> mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in <i>SCN9A</i>, F1624S (novel) and A1632E. 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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.
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.