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The Journal of Neuroscience, November 3, 2004, 24(44):10022-10034; doi:10.1523/JNEUROSCI.2034-04.2004

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 Previous Article

Neurobiology of Disease
A Novel Epilepsy Mutation in the Sodium Channel SCN1A Identifies a Cytoplasmic Domain for {beta} Subunit Interaction

J. Spampanato,1 J. A. Kearney,3 G. de Haan,3 D. P. McEwen,4 A. Escayg,3 I. Aradi,2 B. T. MacDonald,3 S. I. Levin,3 I. Soltesz,2 P. Benna,5 E. Montalenti,5 L. L. Isom,4 A. L. Goldin,1,2 and M. H. Meisler3

Departments of 1Microbiology and Molecular Genetics and 2Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697-4025, Departments of 3Human Genetics and 4Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0618, and 5Department of Neurosciences, University of Torino, 10126 Torino, Italy

A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel {alpha} subunit. The mutation decreased modulation of the {alpha} subunit by {beta}1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of {beta}1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type{alpha} subunit with the {beta}1or {beta}3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for {beta} subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the {alpha} and {beta}1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

Key words: channel; epilepsy; kinetic (kinetics); mutant; sodium (Na); genetics

Received May 26, 2004; revised September 17, 2004; accepted September 17, 2004.




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