Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6)

Jennifer A Kearney; David A Buchner; Georgius De Haan; Maja Adamska; Stephen I Levin; Amy R Furay; Roger L Albin; Julie M Jones; Mauricio Montal; Martin J Stevens; Leslie K Sprunger; Miriam H Meisler

doi:10.1093/hmg/11.22.2765

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Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6)

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Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6)

Jennifer A Kearney, David A Buchner, Georgius De Haan, Maja Adamska, Stephen I Levin, Amy R Furay, Roger L Albin, Julie M Jones, Mauricio Montal, Martin J Stevens, …

Human molecular genetics, Vol.11(22), pp.2765-2775

10/15/2002

DOI: https://doi.org/10.1093/hmg/11.22.2765

Handle:

https://hdl.handle.net/2376/118321

PMID: 12374766

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Abstract

Alternative Splicing

Humans

Muscle, Skeletal - metabolism

RNA, Messenger - metabolism

Ranvier's Nodes - metabolism

RNA Splicing

NAV1.6 Voltage-Gated Sodium Channel

Mice, Mutant Strains

Base Sequence

Sodium Channels - metabolism

Animals, Congenic

Sodium Channels - deficiency

Disease Models, Animal

Neural Conduction - genetics

Movement Disorders - pathology

Mice, Inbred C57BL

RNA, Messenger - genetics

Mice, Inbred C3H

Mice, Knockout

Nerve Tissue Proteins - metabolism

NAV1.1 Voltage-Gated Sodium Channel

Movement Disorders - metabolism

Phenotype

Animals

Alleles

Mice

Sodium Channels - genetics

Movement Disorders - genetics

Muscle, Skeletal - pathology

Mutation

Ranvier's Nodes - pathology

NAV1.2 Voltage-Gated Sodium Channel

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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Title: Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6)
Creators: Jennifer A Kearney - Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor 48109, USA
David A Buchner
Georgius De Haan
Maja Adamska
Stephen I Levin
Amy R Furay
Roger L Albin
Julie M Jones
Mauricio Montal
Martin J Stevens
Leslie K Sprunger
Miriam H Meisler
Publication Details: Human molecular genetics, Vol.11(22), pp.2765-2775
Publisher: England
Grant note: T32 DC00011 / NIDCD NIH HHS NS10692 / NINDS NIH HHS T32 RR07008 / NCRR NIH HHS NS38166 / NINDS NIH HHS T32 HG 00040 / NHGRI NIH HHS NS34509 / NINDS NIH HHS T32 GM07544 / NIGMS NIH HHS
Identifiers: 99900548491001842
Language: English
Resource Type: Journal article