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This Article Full Text Full Text (PDF) All Versions of this Article: 565/2/371    most recent jphysiol.2005.082909v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, F.-f. Articles by Cannon, S. C. Search for Related Content PubMed PubMed Citation Articles by Wu, F.-f. Articles by Cannon, S. C.

¹ Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA
² Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA

Missense mutations in the skeletal muscle sodium channel -subunit gene (SCN4A) 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-aggravated myotonia did not harbour any of the common SCN4A mutations. We therefore screened all 24 exons by denaturing high-performance liquid chromatography, followed by direct sequencing. Two novel missense changes were found with predicted amino acid substitutions: T323M in the DIS5-S6 loop and F1705I in the intracellular C-terminus. The functional impact of these substitutions was assessed by recording whole-cell Na⁺ currents from transiently transfected HEK293 cells. T323M currents were indistinguishable from wild-type (WT). Fast inactivation was impaired for F1705I channels, as demonstrated by an 8.6-mV rightwards shift in voltage dependence and a two-fold 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- 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-terminal mutation in SCN4A 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-terminal mutations in other Na_V channels, the primary effect of F1705I was a partial disruption of fast inactivation.

(Received 9 January 2005; accepted after revision 15 March 2005; first published online 17 March 2005)
Corresponding author S. C. Cannon: Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9036, USA. Email: steve.cannon{at}utsouthwestern.edu

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