{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:16:06Z","timestamp":1773393366403,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2005,6,13]],"date-time":"2005-06-13T00:00:00Z","timestamp":1118620800000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2005,6]]},"abstract":"<jats:p>Missense mutations in the skeletal muscle sodium channel \u03b1\u2010subunit gene (<jats:italic>SCN4A<\/jats:italic>) are associated with a group of clinically overlapping diseases caused by alterations in the excitability of the sarcolemma. Sodium channel defects may increase excitability and cause myotonic stiffness or may render fibres transiently inexcitable to produce periodic paralysis. A patient with cold\u2010aggravated myotonia did not harbour any of the common <jats:italic>SCN4A<\/jats:italic> mutations. We therefore screened all 24 exons by denaturing high\u2010performance liquid chromatography, followed by direct sequencing. Two novel missense changes were found with predicted amino acid substitutions: T323M in the DIS5\u2010S6 loop and F1705I in the intracellular C\u2010terminus. The functional impact of these substitutions was assessed by recording whole\u2010cell Na<jats:sup>+<\/jats:sup> currents from transiently transfected HEK293 cells. T323M currents were indistinguishable from wild\u2010type (WT). Fast inactivation was impaired for F1705I channels, as demonstrated by an 8.6\u2010mV rightwards shift in voltage dependence and a two\u2010fold slowing in the rate of inactivation. Recovery from fast inactivation was not altered, nor was there an increase in the persistent current after a 50\u2010 ms depolarization. Activation and slow inactivation were not appreciably affected. These data suggest that T323M is a benign polymorphism, whereas F1705I results in fast inactivation defects, which are often observed for myotonia. This is the first example of a C\u2010terminal mutation in <jats:italic>SCN4A<\/jats:italic> associated with human disease. Like the cardiac disorders (long QT syndrome type 3 or Brugada syndrome) and generalized epilepsy with febrile seizures plus (GEFS+) associated with C\u2010terminal mutations in other Na<jats:sub>V<\/jats:sub> channels, the primary effect of F1705I was a partial disruption of fast inactivation.<\/jats:p>","DOI":"10.1113\/jphysiol.2005.082909","type":"journal-article","created":{"date-parts":[[2005,3,18]],"date-time":"2005-03-18T04:47:48Z","timestamp":1111121268000},"page":"371-380","source":"Crossref","is-referenced-by-count":38,"title":["A C\u2010terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation"],"prefix":"10.1113","volume":"565","author":[{"given":"Fen\u2010fen","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erynn","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric P.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen C.","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,6,13]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)02360-7"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00914.x"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(91)90064-7"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110204200"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-001-0058-5"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.685bj.x"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.107.5.559"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.52.7.1447"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.17.9549"},{"key":"e_1_2_5_11_1","first-page":"874","article-title":"Visual identification of individual transfected cells for electrophysiology using antibody\u2010coated beads","volume":"17","author":"Jurman ME","year":"1994","journal-title":"Biotechniques"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1999.79.4.1317"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/2.6.745"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211563298"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.3.1215"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200308929"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2034-04.2004"},{"key":"e_1_2_5_18_1","doi-asserted-by":"crossref","first-page":"8610","DOI":"10.1523\/JNEUROSCI.20-23-08610.2000","article-title":"The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation","volume":"23","author":"Struyk AF","year":"2000","journal-title":"J Neurosci"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77249-8"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.26.12785"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00117.2002"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.2005.082909","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.2005.082909","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T03:27:21Z","timestamp":1697254041000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.2005.082909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,6]]},"references-count":20,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2005,6]]}},"alternative-id":["10.1113\/jphysiol.2005.082909"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.2005.082909","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,6]]}}}