S.E.H. and H.K. contributed equally to this work.
Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants
Article first published online: 14 AUG 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 62, Issue 6, pages 560–568, December 2007
How to Cite
Heron, S. E., Khosravani, H., Varela, D., Bladen, C., Williams, T. C., Newman, M. R., Scheffer, I. E., Berkovic, S. F., Mulley, J. C. and Zamponi, G. W. (2007), Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol., 62: 560–568. doi: 10.1002/ana.21169
- Issue published online: 27 DEC 2007
- Article first published online: 14 AUG 2007
- Manuscript Accepted: 29 MAY 2007
- Manuscript Revised: 4 MAY 2007
- Manuscript Received: 8 MAR 2007
- National Health and Medical Research Council of Australia. Grant Number: 144105
- Canadian Institutes of Health Research (CIHR). Grant Number: MOP 49483
- Senior Scholarship of the Alberta Heritage Foundation for Medical Research (AHFMR)
- Canada Research Chair in Molecular Neurobiology
- Studentships from CIHR and the AHFMR
- Postdoctoral fellowship awards from AHFMR
- Heart and Stroke Foundation of Canada
The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures.
Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired.
More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current.
Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case–control study seeking a statistical association. Ann Neurol 2007