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The Journal of Neuroscience, March 4, 2009, 29(9):2733-2741; doi:10.1523/JNEUROSCI.6026-08.2009

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Neurobiology of Disease
The ataxia3 Mutation in the N-Terminal Cytoplasmic Domain of Sodium Channel Na_v1.6 Disrupts Intracellular Trafficking

Lisa M. Sharkey,¹ Xiaoyang Cheng,² Valerie Drews,¹ David A. Buchner,¹ Julie M. Jones,¹ Monica J. Justice,³ Stephen G. Waxman,² Sulayman D. Dib-Hajj,^2 * and Miriam H. Meisler^1 *

¹Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-5618, ²Department of Neurology, Yale University, New Haven, Connecticut 06520-8018, and ³Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Miriam H. Meisler, 4909 Buhl Box 5618, University of Michigan, Ann Arbor, MI 48109-5618. Email: meislerm{at}umich.edu

The ENU-induced neurological mutant ataxia3 was mapped to distal mouse chromosome 15. Sequencing of the positional candidate gene Scn8a encoding the sodium channel Na_v1.6 identified a T>C transition in exon 1 resulting in the amino acid substitution p.S21P near the N terminus of the channel. The cytoplasmic N-terminal region is evolutionarily conserved but its function has not been well characterized. ataxia3 homozygotes exhibit a severe disorder that includes ataxia, tremor, and juvenile lethality. Unlike Scn8a null mice, they retain partial hindlimb function. The mutant transcript is stable but protein abundance is reduced and the mutant channel is not detected in its usual site of concentration at nodes of Ranvier. In whole-cell patch-clamp studies of transfected ND7/23 cells that were maintained at 37°C, the mutant channel did not produce sodium current, and function was not restored by coexpression of β1 and β2 subunits. However, when transfected cells were maintained at 30°C, the mutant channel generated voltage-dependent inward sodium currents with an average peak current density comparable with wild type, demonstrating recovery of channel activity. Immunohistochemistry of primary cerebellar granule cells from ataxia3 mice demonstrated that the mutant protein is retained in the cis-Golgi. This trafficking defect can account for the low level of Na_v1.6-S21P at nodes of Ranvier in vivo and at the surface of transfected cells. The data demonstrate that the cytoplasmic N-terminal domain of the sodium channel is required for anterograde transport from the Golgi complex to the plasma membrane.

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Received July 22, 2008; revised Dec. 18, 2008; accepted Jan. 15, 2009.

Correspondence should be addressed to Miriam H. Meisler, 4909 Buhl Box 5618, University of Michigan, Ann Arbor, MI 48109-5618. Email: meislerm{at}umich.edu

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