title: BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy.
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.
authors.affiliation: Department 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
authors.forename: Deb K
authors.initials: DK
authors.lastname: Pal
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgrafov
authors.forename: Paula
authors.initials: P
authors.lastname: Tabares
authors.forename: Fengli
authors.initials: F
authors.lastname: Zhang
authors.forename: Martina
authors.initials: M
authors.lastname: Durner
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008969:Molecular Sequence Data; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins