Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)
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.
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In the C3H background, medJ mice live a normal lifespan with dystonia and ataxia, with 10% of Scn8a transcripts correctly spliced.
“In the C3H background, medJ mice live a normal lifespan with dystonia and ataxia, with 10% of Scn8a transcripts correctly spliced.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [151]
In a C57Bl/6J background, the same medJ mutation produces only 5% correctly spliced transcript and mice show progressive paralysis and lethality by 1 month of age.
“The same mutation in a C57Bl/6J background produces only 5% correctly spliced transcript and the mice show progressive paralysis and lethality by 1 month of age151.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [151]
Nerve conduction velocity in medJ mutants is decreased by half.
“Nerve conduction velocity in medJ mutants is decreased by half151”
From The neurogenetics of alternative splicing (2016) · cites this paper as [151]
In medJ/C3H mice, replacement of fetal Nav1.2 is delayed and Nav1.6 at the nodes of Ranvier reaches only 10-20% of wild-type levels.
“In medJ/C3H mice, the replacement of fetal Nav1.2 is delayed and the amount of Nav1.6 at the nodes of Ranvier reaches only 10–20% of that seen in wild-type mice.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [151]
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- Authors
- Kearney, J. A.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Kearney, J. A.
- ORCID
- Kearney, J. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-10-15
- Volume
- 11
- Issue
- 22
- Pages
- 2765-2775
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2155947858
- Cited by
- 104
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Institutes of Health (1f32ns010692-01, 5r01ns038166-02)
- National Human Genome Research Institute (T32HG000040)
- National Institute on Deafness and Other Communication Disorders (T32DC000011)
- National Institute of General Medical Sciences (T32GM007544)
- National Institute of Neurological Disorders and Stroke (NS 38166, NS 34509, NS10692, R01NS034509)
- National Center for Research Resources (T32RR007008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- SCN8A, Nav1.6, voltage-gated sodium channels, genetic modifiers, hypomorphic allele, alternative splicing, splice donor site, ataxia, dystonia, tremor, progressive paralysis, nerve conduction velocity, brain metabolism, mouse model
- MeSH terms
- Alleles, Animals, Base Sequence, Disease Models, Animal, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Movement Disorders, Mutation, Nerve Tissue Proteins, Neural Conduction, Phenotype, Ranvier's Nodes, RNA Splicing, RNA, Messenger, Sodium Channels, Alternative Splicing, Mice, Knockout, Muscle, Skeletal, Animals, Congenic, Mice, NAV1.1 Voltage-Gated Sodium Channel, NAV1.2 Voltage-Gated Sodium Channel, NAV1.6 Voltage-Gated Sodium Channel
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