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Volume 16, Number 19, Issue of October 1, 1996 pp. 5993-5999
Copyright ©1996 Society for Neuroscience

A Missense Mutation in the Sodium Channel Scn8a Is Responsible for Cerebellar Ataxia in the Mouse Mutant jolting

Received May 15, 1996; revised July 12, 1996; accepted July 16, 1996.

David C. Kohrman1, Marianne R. Smith2, Alan L. Goldin2, John Harris3, and Miriam H. Meisler1

1 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, 2 Departments of Microbiology and Molecular Genetics, and Physiology and Biophysics, University of California-Irvine, Irvine, California 92717, and 3 Muscular Dystrophy Group Research Laboratories, Regional Neurological Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, United Kingdom

The voltage-gated sodium channel Scn8a is broadly distributed in brain and spinal cord. We have identified a missense mutation in Scn8a that is associated with cerebellar ataxia in the jolting mutant, a mild allele of the ``motor endplate disease'' locus. The jolting mutation results in substitution of Thr for an evolutionarily conserved Ala residue in the cytoplasmic S4-S5 linker of domain III. Introduction of the corresponding mutation into the rat brain IIA sodium channel shifted the voltage dependence of activation by 14 mV in the depolarizing direction, without affecting the kinetics of fast inactivation or recovery from inactivation. A shift in the threshold of the Scn8a channel could account for the reduced spontaneous activity of Purkinje cells, reduced inhibitory output from the cerebellum, and loss of motor control observed in jolting mice.

Key words: sodium channel; ataxia; med; mouse; cerebellum; mutation; Scn8a; Purkinje




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