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Am J Hum Genet. 2003 Aug;73(2):261-70. Epub 2003 Jun 25.

BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy.

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  • 1Department of Biostatistics, Mailman School of Public Health, and Columbia Genome Center, Columbia University and Clinical and Genetic Epidemiology Unit, New York State Psychiatric Institute, New York, 10032, USA. dkp28@columbia.edu

Abstract

Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy that starts in adolescence. A major JME susceptibility locus (EJM1) was mapped to chromosomal region 6p21 in three independent linkage studies, and association was reported between JME and a microsatellite marker in the 6p21 region. The critical region for EJM1 is delimited by obligate recombinants at HLA-DQ and HLA-DP. In the present study, we found highly significant linkage disequilibrium (LD) between JME and a core haplotype of five single-nucleotide-polymorphism (SNP) and microsatellite markers in this critical region, with LD peaking in the BRD2 (RING3) gene (odds ratio 6.45; 95% confidence interval 2.36-17.58). DNA sequencing revealed two JME-associated SNP variants in the BRD2 (RING3) promoter region but no other potentially causative coding mutations in 20 probands from families with positive LOD scores. BRD2 (RING3) is a putative nuclear transcriptional regulator from a family of genes that are expressed during development. Our findings strongly suggest that BRD2 (RING3) is EJM1, the first gene identified for a common idiopathic epilepsy. These findings also suggest that abnormalities of neural development may be a cause of common idiopathic epilepsy, and the findings have implications for the generalizability of proposed pathogenetic mechanisms, derived from diseases that show Mendelian transmission, to their complex counterparts.

PMID:
12830434
[PubMed - indexed for MEDLINE]
PMCID:
PMC1180366
Free PMC Article
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