Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6).
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.
Kearney
Jennifer A
JA
Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor 48109, USA.
Buchner
David A
DA
De Haan
Georgius
G
Adamska
Maja
M
Levin
Stephen I
SI
Furay
Amy R
AR
Albin
Roger L
RL
Jones
Julie M
JM
Montal
Mauricio
M
Stevens
Martin J
MJ
Sprunger
Leslie K
LK
Meisler
Miriam H
MH
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
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