title: Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6).
abstract: 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.
authors.affiliation: Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor 48109, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
authors.forename: David A
authors.initials: DA
authors.lastname: Buchner
authors.forename: Georgius
authors.initials: G
authors.lastname: De Haan
authors.forename: Maja
authors.initials: M
authors.lastname: Adamska
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Levin
authors.forename: Amy R
authors.initials: AR
authors.lastname: Furay
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montal
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stevens
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Sprunger
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D020296:Animals, Congenic; D001483:Base Sequence; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000235:genetics; D010641:Phenotype; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology; D015222:Sodium Channels / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C100681:SCN8A protein, human; C568249:Scn1a protein, mouse; C000654500:Scn2a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels