Abstracts

The first epilepsy locus was mapped in juvenile myoclonic epilepsy (JME) on chromosome (ch) 6p in 1988. Since then the analysis of the ch 6p candidate regions have resulted in conflicting results. More recently, the [italic]EFHC1[/italic] gene, mapped on ch 6p12-p11, was pointed as the causative gene in a few families segregating JME. The aim of our study was to investigate de role of the [italic]EFHC1[/italic] gene and the surrounding candidate regions on ch 6p in JME patients. We performed mutation analysis of the [italic]EFHC1 [/italic]gene in 53 patients with JME and 54 controls by the single-stranded conformation polymorphism (SSCP) method, followed by DNA sequencing. In order to further investigate the candidate regions on ch 6p 21-p11 we performed linkage studies in a total of six unrelated families segregating JME. In addition, we carried out association studies in 44 unrelated JME patients and 63 normal controls. For both, the linkage and association studies, we genotyped eight microsatellite markers on ch 6p (tel. D6S276, D6S265, D6S291, D6S1610, D6S426, D6S271, D6S465 - - D6S257 cent). Two-point and multipoint lod scores were calculated using the LINKAGE software. Significance of association was ascertained by chi-square or Fisher exact test, when appropriated and odds ratio (OR) with 95% confidence interval (CI). We implemented a correction for multiple comparisons and considered significant [italic]p[/italic] values less than 0.01. SSCP analyses detected different patterns of migration for exon 3, in one JME patient and two control subjects, and for exon 4, in three patients. Sequence analyses of exon 3 showed an intronic change (A-G) in one control (SNP rs9349626) and a modification in the coding region resulting in an aminoacid substitution (R182H) in another control subject. Linkage studies resulted in negative lod scores for all markers genotyped and multipoint analysis excluded most of the candidate region on ch 6p21-p11 (lod scores [lt] -2). However, we found significant association between JME and two microsatellite markers (D6S1610 and D6S426). To date, our results failed to identify [italic]EFHC1 [/italic]gene variants that could be related to the JME phenotype. Furthermore, linkage analyses excluded the presence of a major locus predisposing to JME in the [italic]EFHC1 [/italic]region (ch 6p12-p11) and around the [italic]HLA[/italic] locus (ch 6p21). However, the association studies indicate the presence of a locus, in an intermediate region between 6p21 and 6p11-p12, which could be involved in the determination of JME in our group of patients. Additional studies are under way in order to better localize the region identified and search for mutations in candidate genes. (Supported by CAPES and FAPESP.)