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

Kearney, Jennifer A.; Plummer, Nicholas W.; Smith, Marianne R.; Kapur, Jaideep; Cummins, Theodore R.; Waxman, Stephen G.; Goldin, Alan L.; Meisler, Miriam H.

doi:10.1016/s0306-4522(00)00479-6

Cited by 219 publications

(212 citation statements)

References 25 publications

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“…30,31 A small increase in persistent current in SCN2A produces a seizure disorder in transgenic mice. 21 SCN1A mutations responsible for GEFS þ cause only minor changes in channel kinetics. 23,32 Polymorphic sodium channel variants, such as those described here, may contribute to the range of cognitive and emotional function in normal individuals.…”

Section: Discussionmentioning

confidence: 99%

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Sodium channels SCN1A, SCN2A and SCN3A in familial autism

et al. 2003

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Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS þ . To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.

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Section: Discussionmentioning

confidence: 99%

“…20 Mice expressing a mutated SCN2A channel with persistent current exhibit seizures and repetitive behaviors. 21 The association of seizures with mutations in the sodium channel genes, and their location near an autism susceptibility locus, suggested that they might play a role in susceptibility to autism.…”

Section: Introductionmentioning

confidence: 99%

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

et al. 2003

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“…4B). Mutations flanking these sites in the S4-S5 linker DII in human Na ϩ channel genes disrupt slow inactivation (the propensity for Na ϩ channel to inactivate after prolonged usage) and are associated with muscle diseases (16,36).…”

Section: Convergent Amino Acid Replacements In Parts Of the Channel Imentioning

confidence: 99%

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

Zakon

Zwickl

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

126

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We investigated whether the evolution of electric organs and electric signal diversity in two independently evolved lineages of electric fishes was accompanied by convergent changes on the molecular level. We found that a sodium channel gene (Nav1.4a) that is expressed in muscle in nonelectric fishes has lost its expression in muscle and is expressed instead in the evolutionarily novel electric organ in both lineages of electric fishes. This gene appears to be evolving under positive selection in both lineages, facilitated by its restricted expression in the electric organ. This view is reinforced by the lack of evidence for selection on this gene in one electric species in which expression of this gene is retained in muscle. Amino acid replacements occur convergently in domains that influence channel inactivation, a key trait for shaping electric communication signals. Some amino acid replacements occur at or adjacent to sites at which disease-causing mutations have been mapped in human sodium channel genes, emphasizing that these replacements occur in functionally important domains. Selection appears to have acted on the final step in channel inactivation, but complementarily on the inactivation ''ball'' in one lineage, and its receptor site in the other lineage. Thus, changes in the expression and sequence of the same gene are associated with the independent evolution of signal complexity.animal communication ͉ electric organ ͉ channel inactivation ͉ protein evolution ͉ positive selection

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“…The mutation GAL879-881QQQ in sodium channel SCN2A is located in the S4-S5 linker of transmembrane domain 2 and results in delayed inactivation and increased persistent current in Xenopus oocytes. Transgenic mice carrying this mutation exhibit a progressive seizure disorder that begins between 1 and 2 months of age and has several features of human temporal lobe epilepsy (42). Continuous EEG and video monitoring detected focal seizure activity originating in the hippocampus.…”

Section: Temporal Lobe Epilepsy In the Q54 Mouse-mentioning

confidence: 99%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

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

Cited by 219 publications

References 25 publications

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

Identification of Epilepsy Genes in Human and Mouse

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