Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 73, Issue 2, Pages 261-270Publisher
CELL PRESS
DOI: 10.1086/377006
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Funding
- NIDDK NIH HHS [DK31775, R01 DK031775] Funding Source: Medline
- NIMH NIH HHS [MH48858, R01 MH048858] Funding Source: Medline
- NINDS NIH HHS [R01 NS037466, NS37466, NS27941, R01 NS027941] Funding Source: Medline
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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.
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