{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T20:02:29Z","timestamp":1770235349409,"version":"3.49.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":197,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["JP18K07524"],"award-info":[{"award-number":["JP18K07524"]}]},{"name":"Intractable Disease from the Ministry of Health, Labour and Welfare","award":["20FC1036"],"award-info":[{"award-number":["20FC1036"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19ek0109230"],"award-info":[{"award-number":["JP19ek0109230"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19bm0804005"],"award-info":[{"award-number":["JP19bm0804005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS KAKENHI","award":["JP15K09314"],"award-info":[{"award-number":["JP15K09314"]}]},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health","award":["AR063182"],"award-info":[{"award-number":["AR063182"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called \u2018gating pore currents\u2019, and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa103","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T17:46:02Z","timestamp":1594921562000},"source":"Crossref","is-referenced-by-count":14,"title":["Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor"],"prefix":"10.1093","volume":"2","author":[{"given":"Tomoya","family":"Kubota","sequence":"first","affiliation":[{"name":"Division of Health Sciences, Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 5650871, Japan"},{"name":"Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"},{"name":"Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fenfen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savine","family":"Vicart","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Assistance Publique -H\u00f4pitaux de Paris, Center of Research in Myology-UMR 974, Service of Neuro-Myology (CMR Muscle Channelopathies), Institute of Myology, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Nakaza","sequence":"additional","affiliation":[{"name":"Division of Health Sciences, Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 5650871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damien","family":"Sternberg","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Assistance Publique -H\u00f4pitaux de Paris, Center of Research in Myology-UMR 974, Service of Neuro-Myology (CMR Muscle Channelopathies), Institute of Myology, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Hakone Hospital, Odawara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuru","family":"Furuta","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"},{"name":"Department of Neurology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Kokunai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"},{"name":"Sorbonne Universit\u00e9, INSERM, Assistance Publique -H\u00f4pitaux de Paris, Center of Research in Myology-UMR 974, Service of Neuro-Myology (CMR Muscle Channelopathies), Institute of Myology, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Hakone Hospital, Odawara, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norito","family":"Kokubun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Dokkyo Medical University, Tochigi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Assistance Publique -H\u00f4pitaux de Paris, Center of Research in Myology-UMR 974, Service of Neuro-Myology (CMR Muscle Channelopathies), Institute of Myology, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen C","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5513-5012","authenticated-orcid":false,"given":"Masanori P","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Health Sciences, Department of Functional Diagnostic Science, Osaka University Graduate 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