A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

J. A. Kearney; N. W. Plummer; M. R. Smith; J. Kapur; T. R. Cummins; S. G. Waxman; A. L. Goldin; M. H. Meisler

doi:10.1016/S0306-4522(00)00479-6

A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

J. A. Kearney, N. W. Plummer, M. R. Smith, J. Kapur, T. R. Cummins, S. G. Waxman, A. L. Goldin, M. H. Meisler^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

208 Scopus citations

Abstract

The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Na_v1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.

Original language	English (US)
Pages (from-to)	307-317
Number of pages	11
Journal	Neuroscience
Volume	102
Issue number	2
DOIs	https://doi.org/10.1016/S0306-4522(00)00479-6
State	Published - Jan 15 2001

Funding

We thank Julie Jones and Laurie Weiss for advice and assistance, Leslie Sprunger for helpful discussions, and Sally Camper and Roger Albin for review of the manuscript. Supported by NIH grants NS34509 (MHM) and NS26729 (ALG), the Organogenesis Postdoctoral Training Program T32 HD07505 and National Research Service Award NS10692 (JAK), NINDS awards KO8 NS01748 and KO2 NS02081 (JK), and National Multiple Sclerosis Grant RG1912 and grants from the Medical Research Service and Rehabilitation Research Service, Veterans Administration (SGW). We acknowledge Thomas Saunders and Mark Berard, and the Transgenic Animal Model Core of the University of Michigan Biomedical Research Core Facilities, for preparation of transgenic mice. Transgenic Animal Core support was provided by the University of Michigan Center for Organogenesis and the University of Michigan Cancer Center, NIH CA46592.

Keywords

Channelopathy
Epilepsy
Mouse mutant
Neurological disease

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0306-4522(00)00479-6

Cite this

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title = "A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities",

abstract = "The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Nav1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.",

keywords = "Channelopathy, Epilepsy, Mouse mutant, Neurological disease",

author = "Kearney, {J. A.} and Plummer, {N. W.} and Smith, {M. R.} and J. Kapur and Cummins, {T. R.} and Waxman, {S. G.} and Goldin, {A. L.} and Meisler, {M. H.}",

note = "Funding Information: We thank Julie Jones and Laurie Weiss for advice and assistance, Leslie Sprunger for helpful discussions, and Sally Camper and Roger Albin for review of the manuscript. Supported by NIH grants NS34509 (MHM) and NS26729 (ALG), the Organogenesis Postdoctoral Training Program T32 HD07505 and National Research Service Award NS10692 (JAK), NINDS awards KO8 NS01748 and KO2 NS02081 (JK), and National Multiple Sclerosis Grant RG1912 and grants from the Medical Research Service and Rehabilitation Research Service, Veterans Administration (SGW). We acknowledge Thomas Saunders and Mark Berard, and the Transgenic Animal Model Core of the University of Michigan Biomedical Research Core Facilities, for preparation of transgenic mice. Transgenic Animal Core support was provided by the University of Michigan Center for Organogenesis and the University of Michigan Cancer Center, NIH CA46592. ",

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doi = "10.1016/S0306-4522(00)00479-6",

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T1 - A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

AU - Kearney, J. A.

AU - Plummer, N. W.

AU - Smith, M. R.

AU - Kapur, J.

AU - Cummins, T. R.

AU - Waxman, S. G.

AU - Goldin, A. L.

AU - Meisler, M. H.

N1 - Funding Information: We thank Julie Jones and Laurie Weiss for advice and assistance, Leslie Sprunger for helpful discussions, and Sally Camper and Roger Albin for review of the manuscript. Supported by NIH grants NS34509 (MHM) and NS26729 (ALG), the Organogenesis Postdoctoral Training Program T32 HD07505 and National Research Service Award NS10692 (JAK), NINDS awards KO8 NS01748 and KO2 NS02081 (JK), and National Multiple Sclerosis Grant RG1912 and grants from the Medical Research Service and Rehabilitation Research Service, Veterans Administration (SGW). We acknowledge Thomas Saunders and Mark Berard, and the Transgenic Animal Model Core of the University of Michigan Biomedical Research Core Facilities, for preparation of transgenic mice. Transgenic Animal Core support was provided by the University of Michigan Center for Organogenesis and the University of Michigan Cancer Center, NIH CA46592.

PY - 2001/1/15

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N2 - The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Nav1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.

AB - The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Nav1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.

KW - Channelopathy

KW - Epilepsy

KW - Mouse mutant

KW - Neurological disease

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ER -

A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

Abstract

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Keywords

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