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The Journal of Neuroscience, March 17, 2004, 24(11):2690-2698; doi:10.1523/JNEUROSCI.3089-03.2004

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Cellular/Molecular
A Nonsense Mutation of the Sodium Channel Gene SCN2A in a Patient with Intractable Epilepsy and Mental Decline

Kazusaku Kamiya,¹ Makoto Kaneda,² Takashi Sugawara,¹ Emi Mazaki,¹ Nami Okamura,¹ Mauricio Montal,³ Naomasa Makita,⁴ Masaki Tanaka,⁵ Katsuyuki Fukushima,⁵ Tateki Fujiwara,⁵ Yushi Inoue,⁵ and Kazuhiro Yamakawa¹

¹Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama 351-0198, Japan, ²Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, ³Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, ⁴Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, and ⁵National Epilepsy Center, Shizuoka Medical Institute of Neurological Disorders, Shizuoka 420-8688, Japan

Mutations, exclusively missense, of voltage-gated sodium channel subunit type 1 (SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and frameshift mutations of SCN1A, by contrast, were identified in intractable epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline. The phenotype is similar to SMEI but distinct because of partial epilepsy, delayed onset (1 year 7 months), and absence of temperature sensitivity. A mutational analysis revealed that the patient had a heterozygous de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na_v1.2 wild-type channels and the R102X mutant protein coexpressed in human embryonic kidney 293 cells showed that the truncated mutant protein shifted the voltage dependence of inactivation of wild-type channels in the hyperpolarizing direction. Analysis of the subcellular localization of R102X truncated protein suggested that its dominant negative effect could arise from direct or indirect cytoskeletal interactions of the mutant protein. Haploinsufficiency of Na_v1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy.

Key words: SCN2A; sodium channel; nonsense mutation; epilepsy; mental decline; dominant negative

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Received June 26, 2003; revised January 19, 2004; accepted January 19, 2004.

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