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Human Molecular Genetics, 2002, Vol. 11, No. 22 2765-2775
© 2002 Oxford University Press

Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

Jennifer A. Kearney1, David A. Buchner1, Georgius de Haan1, Maja Adamska1, Stephen I. Levin1, Amy R. Furay2, Roger L. Albin2,4, Julie M. Jones1, Mauricio Montal5, Martin J. Stevens3, Leslie K. Sprunger1 and Miriam H. Meisler1,*

1Department of Human Genetics, 2Department of Neurology and 3Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA, 4Ann Arbor Veterans Affairs Medical Center Geriatric Research, Education, and Clinical Center, Ann Arbor, MI 48105, USA and 5Division of Biology, Section of Neurobiology, University of California at San Diego, La Jolla, CA 92093, USA

Received June 26, 2002; Accepted August 16, 2002

Scn8a encodes an abundant, widely distributed voltage-gated sodium channel found throughout the central and peripheral nervous systems. Mice with different mutant alleles of Scn8a provide models of the movement disorders ataxia, dystonia, tremor and progressive paralysis. We previously reported that the phenotype of the hypomorphic allele of Scn8a, medJ, is dependent upon an unlinked modifier locus, Scnm1. Strain C57BL/6J carries a sensitive allele of the modifier locus that results in juvenile lethality. We now provide evidence that the modifier acts on the splicing efficiency of the mutant splice donor site. Mutant mice display either 90% or 95% reduction in the proportion of correctly spliced mRNA, depending on modifier genotype. The abundance of the channel protein, Nav1.6, is also reduced by an order of magnitude in medJ mice, resulting in delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass and reduction of brain metabolic activity. medJ mice provide a model for the physiological effects of sodium channel deficiency and the molecular mechanism of bigenic disease.

* To whom correspondence should be addressed at: University of Michigan, 4808 Medical Science II, Ann Arbor, MI 48109-0618, USA. Tel: +1 7347635546; Fax: +1 7347639691; Email: meislerm{at}umich.edu


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