QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 8, 2006, 26(10):2714-2723; doi:10.1523/JNEUROSCI.2977-05.2006

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science 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 ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Barela, A. J. Articles by Escayg, A. Search for Related Content PubMed PubMed Citation Articles by Barela, A. J. Articles by Escayg, A.

 Previous Article  |  Next Article 

Cellular/Molecular
An Epilepsy Mutation in the Sodium Channel SCN1A That Decreases Channel Excitability

Arthur J. Barela,^1 * Salina P. Waddy,^2 * Jay G. Lickfett,¹ Jessica Hunter,³ Aimee Anido,³ Sandra L. Helmers,² Alan L. Goldin,¹ and Andrew Escayg³

¹Department of Microbiology and Molecular Genetics, University of California at Irvine, Irvine, California 92697-4025, and Departments of ²Neurology and ³Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia 30322

Correspondence should be address to Andrew Escayg at the above address. Email: aescayg{at}genetics.emory.edu

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABA_A receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFS+). A novel mutation, R859C, in the Na_v1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Na_v1.1 channel subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Na_v1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations, which have changes predicted to increase neuronal firing.

Key words: epilepsy; sodium channel; electrophysiology; mutation; GEFS+; SCN1A

---

Received July 19, 2005; revised Jan. 20, 2006; accepted Jan. 24, 2006.

Correspondence should be address to Andrew Escayg at the above address. Email: aescayg{at}genetics.emory.edu

This article has been cited by other articles:

				K. M. Kahlig, S. N. Misra, and A. L. George Jr Impaired Inactivation Gate Stabilization Predicts Increased Persistent Current for an Epilepsy-Associated SCN1A Mutation J. Neurosci., October 25, 2006; 26(43): 10958 - 10966. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help