Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders
Jun-Hui Yuan
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorXiaoyang Cheng
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorEiji Matsuura
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorYujiro Higuchi
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorMasahiro Ando
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorAkihiro Hashiguchi
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorAkiko Yoshimura
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorRyo Nakachi
Department of Neurology, National Hospital Organization Okinawa Hospital, Okinawa, Japan
Search for more papers by this authorJun Mine
Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorTakeshi Taketani
Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
Search for more papers by this authorKenichi Maeda
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorSaori Kawakami
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorRyutaro Kira
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorShoko Tanaka
Department of Neurology, Fukushima Medical University, Fukushima, Japan
Search for more papers by this authorKazuaki Kanai
Department of Neurology, Fukushima Medical University, Fukushima, Japan
Search for more papers by this authorFadia Dib-Hajj
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorSulayman D. Dib-Hajj
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorCorresponding Author
Stephen G. Waxman
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Correspondence
Stephen G. Waxman, Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA.
Email: [email protected]
Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8520, Japan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Hiroshi Takashima
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Correspondence
Stephen G. Waxman, Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA.
Email: [email protected]
Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8520, Japan.
Email: [email protected]
Search for more papers by this authorJun-Hui Yuan
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorXiaoyang Cheng
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorEiji Matsuura
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorYujiro Higuchi
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorMasahiro Ando
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorAkihiro Hashiguchi
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorAkiko Yoshimura
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Search for more papers by this authorRyo Nakachi
Department of Neurology, National Hospital Organization Okinawa Hospital, Okinawa, Japan
Search for more papers by this authorJun Mine
Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorTakeshi Taketani
Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
Search for more papers by this authorKenichi Maeda
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorSaori Kawakami
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorRyutaro Kira
Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan
Search for more papers by this authorShoko Tanaka
Department of Neurology, Fukushima Medical University, Fukushima, Japan
Search for more papers by this authorKazuaki Kanai
Department of Neurology, Fukushima Medical University, Fukushima, Japan
Search for more papers by this authorFadia Dib-Hajj
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorSulayman D. Dib-Hajj
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Search for more papers by this authorCorresponding Author
Stephen G. Waxman
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
Correspondence
Stephen G. Waxman, Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA.
Email: [email protected]
Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8520, Japan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Hiroshi Takashima
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Correspondence
Stephen G. Waxman, Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA.
Email: [email protected]
Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8520, Japan.
Email: [email protected]
Search for more papers by this authorJun-Hui Yuan and Xiaoyang Cheng contributed equally to this work.
Stephen G. Waxman and Hiroshi Takashima contributed equally to this work.
Abstract
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.
CONFLICT OF INTEREST STATEMENT
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Supporting Information
| Filename | Description |
|---|---|
| jns12590-sup-0001-TableS1.docxWord 2007 document , 14.5 KB | TABLE S1: Clinical features of four undiagnosed patients with EM/EM-like pain disorders |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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