{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:28:38Z","timestamp":1791890918423,"version":"4.3.4"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,8,15]]},"abstract":"<jats:p>The pathomechanism of familial hypokalemic periodic paralysis\n (HypoPP) is a mystery, despite knowledge of the underlying\n dominant point mutations in the dihydropyridine receptor (DHPR) voltage\n sensor. In five HypoPP families without DHPR gene defects, we\n identified two mutations, Arg-672\u2192His and \u2192Gly, in the voltage\n sensor of domain 2 of a different protein: the skeletal muscle sodium\n channel \u03b1 subunit, known to be responsible for hereditary muscle\n diseases associated with myotonia. Excised skeletal muscle fibers from\n a patient heterozygous for Arg-672\u2192Gly displayed depolarization and\n weakness in low-potassium extracellular solution. Slowing and smaller\n size of action potentials were suggestive of excitability of the\n wild-type channel population only. Heterologous expression of the two\n sodium channel mutations revealed a 10-mV left shift of the\n steady-state fast inactivation curve enhancing inactivation and a\n sodium current density that was reduced even at potentials at which\n inactivation was removed. Decreased current and small action potentials\n suggested a low channel protein density. The alterations are decisive\n for the pathogenesis of episodic muscle weakness by reducing the number\n of excitable sodium channels particularly at sustained membrane\n depolarization. The results prove that SCN4A, the gene encoding the\n sodium channel \u03b1 subunit of skeletal muscle is responsible for\n HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2\n represents a disease caused by enhanced channel inactivation and\n current reduction showing no myotonia.<\/jats:p>","DOI":"10.1073\/pnas.97.17.9549","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:44Z","timestamp":1027679504000},"page":"9549-9554","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":222,"title":["Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current"],"prefix":"10.1073","volume":"97","author":[{"given":"Karin","family":"Jurkat-Rott","sequence":"first","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nenad","family":"Mitrovic","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Hang","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Kouzmenkine","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Iaizzo","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Herzog","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Lerche","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Nicole","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Vale-Santos","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Chauveau","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Lehmann-Horn","sequence":"additional","affiliation":[{"name":"Departments of Applied Physiology and\r Neurology, Ulm University, D-89081 Germany;\r Department of Anesthesiology, University of Minnesota,\r Minneapolis, MN 55455; Department of Neurology,\r Ludwig-Maximilians University, Munich, Germany; Institut\r National de la Sant\u00e9 et de la Recherche M\u00e9dicale and\r F\u00e9d\u00e9ration de Neurologie, Facult\u00e9 de M\u00e9decine\r et Groupe Hospitalier Piti\u00e9-Salp\u00eatri\u00e8re, Paris,\r France; Department of Neurology, Lisboa, Portugal; and\r Department of Nephrology, Groupe Hospitalier\r..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,8,15]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"1304","volume-title":"Myology","author":"Lehmann-Horn F","year":"1994","unstructured":"F Lehmann-Horn, A Engel, R R\u00fcdel, K Ricker Myology, eds A G Engel, C Franzini-Armstrong (McGraw-Hill, New York), pp. 1304\u20131334 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