Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia.
The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3 Hz spike-wave EEG is one of the most common human epilepsies, and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike-wave EEG, with frequencies in the range of 5-7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3 Hz spike-wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming alpha1A subunit of CaV2.1 channels (CaV2.1alpha1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1alpha1, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.
Imbrici
Paola
P
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG.
Jaffe
Stephen L
SL
Eunson
Louise H
LH
Davies
Nicholas P
NP
Herd
Colin
C
Robertson
Robert
R
Kullmann
Dimitri M
DM
Hanna
Michael G
MG
D000328:Adult; D000818:Animals; D015220:Calcium Channels / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000502:physiology*; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D014982:Xenopus laevis
D015220:Calcium Channels; D020864:Calcium Channels, N-Type; C105656:CACNA1A protein, human