{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T02:29:11Z","timestamp":1776824951551,"version":"3.51.2"},"reference-count":52,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2017,10,15]],"date-time":"2017-10-15T00:00:00Z","timestamp":1508025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31270878"],"award-info":[{"award-number":["31270878"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81527901"],"award-info":[{"award-number":["81527901"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","award":["2014CB910302"],"award-info":[{"award-number":["2014CB910302"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LY16H090007"],"award-info":[{"award-number":["LY16H090007"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LY12C05004"],"award-info":[{"award-number":["LY12C05004"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,11,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Paramyotonia congenita is a hereditary channelopathy caused by missense mutations in the <jats:italic>SCN4A<\/jats:italic> gene, which encodes the \u03b1 subunit of the human skeletal muscle voltage\u2010gated sodium channel NaV1.4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Affected individuals suffered from myotonia and paralysis of muscles, which were aggravated by exposure to cold.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We report a three\u2010generation Chinese family with patients presenting paramyotonia congenita and identify a novel N1366S mutation of NaV1.4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Whole\u2010cell electrophysiological recordings of the N1366S channel reveal a gain\u2010of\u2010function change of gating in response to cold. Modelling and molecular dynamic simulation data suggest that an arginine\u2010to\u2010serine substitution at position 1366 increases the distance from N1366 to R1454 and disrupts the hydrogen bond formed between them at low temperature.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We demonstrate that N1366S is a disease\u2010causing mutation and that the temperature\u2010sensitive alteration of N1366S channel activity may be responsible for the pronounced paramyotonia congenita symptoms of these patients.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Paramyotonia congenita is an autosomal dominant skeletal muscle channelopathy caused by missense mutations in <jats:italic>SCN4A<\/jats:italic>, the gene encoding the \u03b1 subunit of the human skeletal muscle voltage\u2010gated sodium channel NaV1.4. We report a three\u2010generation family in which six members present clinical symptoms of paramyotonia congenita characterized by a marked worsening of myotonia by cold and by the presence of clear episodes of paralysis. We identified a novel mutation in <jats:italic>SCN4A<\/jats:italic> (Asn1366Ser, N1366S) in all patients in the family but not in healthy relatives or in 500 normal control subjects. Functional analysis of the channel protein expressed in HEK293 cells by whole\u2010cell patch clamp recording revealed that the N1366S mutation led to significant alterations in the gating process of the NaV1.4 channel. The N1366S mutant displayed a cold\u2010induced hyperpolarizing shift in the voltage dependence of activation and a depolarizing shift in fast inactivation, as well as a reduced rate of fast inactivation and accelerated recovery from fast inactivation. In addition, homology modelling and molecular dynamic simulation of N1366S and wild\u2010type NaV1.4 channels indicated that the arginine\u2010to\u2010serine substitution disrupted the hydrogen bond formed between N1366 and R1454. Together, our results suggest that N1366S is a gain\u2010of\u2010function mutation of NaV1.4 at low temperature and the mutation may be responsible for the clinical symptoms of paramyotonia congenita in the affected family and constitute a basis for studies into its pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274877","type":"journal-article","created":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T11:39:12Z","timestamp":1505907552000},"page":"6837-6850","source":"Crossref","is-referenced-by-count":16,"title":["N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita"],"prefix":"10.1113","volume":"595","author":[{"given":"Qing","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Ye","sequence":"additional","affiliation":[{"name":"Department 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