An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene
Article first published online: 28 AUG 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 64, Issue 2, pages 158–167, August 2008
How to Cite
Kapoor, A., Satishchandra, P., Ratnapriya, R., Reddy, R., Kadandale, J., Shankar, S. K. and Anand, A. (2008), An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol., 64: 158–167. doi: 10.1002/ana.21428
- Issue published online: 28 AUG 2008
- Article first published online: 28 AUG 2008
- Manuscript Accepted: 25 APR 2008
- Manuscript Revised: 21 APR 2008
- Manuscript Received: 9 AUG 2007
- DBT. Grant Number: BT/PR1414/Med/13/050/98
- DAE. Grant Number: 2005/21/10-BRNS/1166
- JNCASR. Grant Number: JNC/PC-19
To identify the disease locus in a three-generation south Indian family having several of its members affected with idiopathic epilepsy.
Genome-wide parametric linkage analysis was performed with 382 autosomal markers. Mutational analysis of the positional candidate genes in linked interval was performed by direct sequencing of genomic DNA from the proband in the family. Expression analysis in human adult brain was performed by Western blotting.
A novel epilepsy genetic locus on chromosome 3q13.3-q21 was identified by linkage analysis. This locus comprises about 12 megabases of the genomic interval, with its proximal and distal genetic boundaries defined by microsatellite markers, D3S3675 and D3S1551, respectively. In this interval, we found a novel, patient-specific, missense variant, Arg898Gln, at the extracellular calcium sensing receptor (CASR), a gene belonging to the G-protein–coupled receptor family. CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy.
A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3-q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary-conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders. Ann Neurol 2008;64:158–167