Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

77 Citations (Scopus)

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, Nav1.6, 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.

Original languageEnglish (US)
Pages (from-to)2765-2775
Number of pages11
JournalHuman molecular genetics
Volume11
Issue number22
StatePublished - Oct 15 2002

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Modifier Genes
Sodium Channels
Alleles
Ranvier's Nodes
Voltage-Gated Sodium Channels
RNA Splice Sites
Dystonia
Neural Conduction
Peripheral Nervous System
Movement Disorders
Tremor
Ataxia
Paralysis
Central Nervous System
Genotype
Phenotype
Muscles
Messenger RNA
Brain
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kearney, J. A., Buchner, D. A., De Haan, G., Adamska, M., Levin, S. I., Furay, A. R., ... Meisler, M. H. (2002). Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6). Human molecular genetics, 11(22), 2765-2775.
Kearney, Jennifer A. ; Buchner, David A. ; De Haan, Georgius ; Adamska, Maja ; Levin, Stephen I. ; Furay, Amy R. ; Albin, Roger L. ; Jones, Julie M. ; Montal, Mauricio ; Stevens, Martin J. ; Sprunger, Leslie K. ; Meisler, Miriam H. / Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6). In: Human molecular genetics. 2002 ; Vol. 11, No. 22. pp. 2765-2775.
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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, Nav1.6, 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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Kearney, JA, Buchner, DA, De Haan, G, Adamska, M, Levin, SI, Furay, AR, Albin, RL, Jones, JM, Montal, M, Stevens, MJ, Sprunger, LK & Meisler, MH 2002, 'Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)', Human molecular genetics, vol. 11, no. 22, pp. 2765-2775.

Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6). / Kearney, Jennifer A.; Buchner, David A.; De Haan, Georgius; Adamska, Maja; Levin, Stephen I.; Furay, Amy R.; Albin, Roger L.; Jones, Julie M.; Montal, Mauricio; Stevens, Martin J.; Sprunger, Leslie K.; Meisler, Miriam H.

In: Human molecular genetics, Vol. 11, No. 22, 15.10.2002, p. 2765-2775.

Research output: Contribution to journalArticle

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T1 - Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

AU - Kearney, Jennifer A.

AU - Buchner, David A.

AU - De Haan, Georgius

AU - Adamska, Maja

AU - Levin, Stephen I.

AU - Furay, Amy R.

AU - Albin, Roger L.

AU - Jones, Julie M.

AU - Montal, Mauricio

AU - Stevens, Martin J.

AU - Sprunger, Leslie K.

AU - Meisler, Miriam H.

PY - 2002/10/15

Y1 - 2002/10/15

N2 - 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, Nav1.6, 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.

AB - 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, Nav1.6, 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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