{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T17:59:13Z","timestamp":1776621553730,"version":"3.51.2"},"reference-count":21,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"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":["JP21bm0804005"],"award-info":[{"award-number":["JP21bm0804005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI (JP18K07524)"],"award-info":[{"award-number":["KAKENHI (JP18K07524)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI(JP22K07493)"],"award-info":[{"award-number":["KAKENHI(JP22K07493)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["the Research Grant for Intractable Disease(20FC103"],"award-info":[{"award-number":["the Research Grant for Intractable Disease(20FC103"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"publisher","award":["Research grant"],"award-info":[{"award-number":["Research grant"]}],"id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["Grant for medical science research"],"award-info":[{"award-number":["Grant for medical science research"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction\/Aims<\/jats:title><jats:p>Mutations in the <jats:italic>SCN4A<\/jats:italic> gene encoding a voltage\u2010gated sodium channel (Nav1.4) cause hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). Typically, both HyperPP and HypoPP are considered as monogenic disorders caused by a missense mutation with a large functional effect. However, a few cases with atypical periodic paralysis phenotype have been caused by multiple mutations in ion\u2010channel genes expressed in skeletal muscles. In this study we investigated the underlying pathogenic mechanisms in such cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We clinically assessed two families: proband 1 with HyperPP and proband 2 with atypical periodic paralysis with hypokalemia. Genetic analyses were performed by next\u2010generation sequencing and conventional Sanger sequencing, followed by electrophysiological analyses of the mutant Nav1.4 channels expressed in human embryonic kidney 293T (HEK293T) cells using the whole\u2010cell patch\u2010clamp technique.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In proband 1, K880del was identified in the <jats:italic>SCN4A<\/jats:italic> gene. In proband 2, K880del and a novel mutation, R1639H, were identified in the same allele of the <jats:italic>SCN4A<\/jats:italic> gene. Functional analyses revealed that the K880del in <jats:italic>SCN4A<\/jats:italic> has a weak functional effect on hNav1.4, increasing the excitability of the sarcolemma, which could represent a potential pathogenic factor. Although R1639H alone did not reveal functional changes strong enough to be pathogenic, Nav1.4 with both K880del and R1639H showed enhanced activation compared with K880del alone, indicating that R1639H may modify the hNav1.4 channel function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>A cumulative effect of variants with small functional alterations may be considered as the underpinning oligogenic pathogenic mechanisms for the unusual phenotype of periodic paralysis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mus.27725","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T19:14:31Z","timestamp":1663528471000},"page":"757-761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Periodic paralysis due to cumulative effects of rare variants in <scp><i>SCN4A<\/i><\/scp> with small functional alterations"],"prefix":"10.1002","volume":"66","author":[{"given":"Maki","family":"Shibano","sequence":"first","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences Osaka University Graduate School of Medicine  Suita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-8537","authenticated-orcid":false,"given":"Tomoya","family":"Kubota","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences Osaka University Graduate School of Medicine  Suita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norito","family":"Kokubun","sequence":"additional","affiliation":[{"name":"Department of Neurology Dokkyo Medical University  Shimotsuga Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Miyaji","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Medicine Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Kuriki","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzuru","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Yokohama City University Medical Center  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruka","family":"Hamanoue","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"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":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences Osaka University Graduate School of Medicine  Suita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c140062"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.29.051605.112815"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.52.7.1447"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/124.6.1091"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05598"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa103"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202112946"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.08.030"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9654"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv352"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1230273100"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.082909"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201400821"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2016.1212140"},{"key":"e_1_2_11_16_1","first-page":"388","article-title":"Den\u2010i izonsei Na channeru (SCN4A) idenshi ni hen\u2010i wo mitometa myotonia permanens no 1 rei","volume":"42","author":"Kibe T","year":"2010","journal-title":"No To Hattatsu."},{"key":"e_1_2_11_17_1","unstructured":"Genome Aggregation Database (gnomAD).https:\/\/gnomad.broadinstitute.org. Accessed December 24 2021."},{"key":"e_1_2_11_18_1","unstructured":"Human Genetic Variation Database.https:\/\/www.hgvd.genome.med.kyoto\u2010u.ac.jp. Accessed December 24 2021."},{"key":"e_1_2_11_19_1","unstructured":"Japanese Multi Omics Reference Panel.https:\/\/jmorp.megabank.tohoku.ac.jp\/202109. Accessed December 24 2021."},{"key":"e_1_2_11_20_1","unstructured":"Combined Annotation Dependent Depletion (CADD).https:\/\/cadd.gs.washington.edu. Accessed December 24 2021."},{"key":"e_1_2_11_21_1","unstructured":"PROVEAN.http:\/\/provean.jcvi.org\/index.php. Accessed December 24 2021."},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12880"}],"container-title":["Muscle &amp; Nerve"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27725","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mus.27725","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mus.27725","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:54:57Z","timestamp":1692633297000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mus.27725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,4]]},"references-count":21,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/mus.27725"],"URL":"https:\/\/doi.org\/10.1002\/mus.27725","archive":["Portico"],"relation":{},"ISSN":["0148-639X","1097-4598"],"issn-type":[{"value":"0148-639X","type":"print"},{"value":"1097-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,4]]},"assertion":[{"value":"2022-01-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}