EVIDENCE SUGGESTING BRD2 IS THE EJM1 LOCUS FOR JUVENILE MYOCLONIC EPILEPSY
Abstract number :
3.083
Submission category :
Year :
2002
Submission ID :
695
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Deb K. Pal, Oleg Evgrafov, Martina Durner, Conrad Gilliam, David A. Greenberg. Mailman School of Public Health, Columbia University, New York, NY; Columbia Genome Center, Columbia University, New York, NY
RATIONALE: Several reports have demonstrated linkage of juvenile myoclonic epilepsy to the HLA region of chromosome 6. Our group found statistically significant evidence of association to alleles at the DQB1 and RING3 (BRD2) loci (1). The objectives of the present study were to define the region of interest more precisely using densely spaced SNP markers and to identify possible causative mutations.
METHODS: 20 JME probands, taken from families showing moderate to strong evidence for linkage (Iod[gt]0.1) to the 6p locus, and 46 unlinked JME probands, were typed for 11 SNPs in the region between HLA-DP and HLA-DQ. SNPs were typed using the technique of fluorescent polarization. Haplotype frequencies were compared in a case-control design, and also using the program SNPHAP (2). Additionally, all exons and splice sites in the region were tested for mutations in all four linked families.
RESULTS: One consistent haplotype was identified in linked JME probands, which was significantly more frequent than in comparison chromosomes (Odds ratio: 5.8, 95% CI:1.7-19.4, p=0.001). This haplotype extended to the boundary of the BRD2 gene and contained the CA repeat allele with which we had originally demonstrated association. There was no significant evidence of linkage disequilibrium beyond the gene boundaries. Similar results were obtained through SNPHAP - the same consistent haplotype was predicted with highest probability in JME linked probands more than twice as often as in comparison chromosomes. Sequencing did not reveal any mutations that would lead to changes in amino-acids.
CONCLUSIONS: Other reports of loci in common disease also have failed to find consistent mutations in exons in loci which show association. While we cannot yet definitively exclude the rest of the DQ-DP HLA region, the presence of a SNP haplotype, together with our previous evidence of association with an allele of a microsatellite marker only in linked families, continues to suggest that BRD2 is EJM1.
1. Greenberg DA, Durner M, Keddache M, et al. Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet. 2000 Feb;66(2):508-16.
2. www-gene.cimr.cam.ac.uk/clayton/software/snphap.txt
[Supported by: NIH grants: DK31775, NS27941, MH48858, NS37466.]