Journal
HUMAN MOLECULAR GENETICS
Volume 11, Issue 22, Pages 2765-2775Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/11.22.2765
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Funding
- NCRR NIH HHS [T32 RR07008] Funding Source: Medline
- NHGRI NIH HHS [T32 HG 00040] Funding Source: Medline
- NIDCD NIH HHS [T32 DC00011] Funding Source: Medline
- NIGMS NIH HHS [T32 GM07544] Funding Source: Medline
- NINDS NIH HHS [NS34509, NS38166, NS10692] Funding Source: Medline
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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, Na-v 1.6, 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.
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