title: Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.
abstract: A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.
authors.affiliation: Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, Gower Street Campus, 5 University Street, London WC1E 6JJ, UK. n.taske@ucl.ac.uk
authors.forename: Nichole L
authors.initials: NL
authors.lastname: Taske
authors.forename: Magali P
authors.initials: MP
authors.lastname: Williamson
authors.forename: Andrew
authors.initials: A
authors.lastname: Makoff
authors.forename: Louise
authors.initials: L
authors.lastname: Bate
authors.forename: David
authors.initials: D
authors.lastname: Curtis
authors.forename: Michael
authors.initials: M
authors.lastname: Kerr
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Kjeldsen
authors.forename: Kiang An
authors.initials: KA
authors.lastname: Pang
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.forename: Mogens L
authors.initials: ML
authors.lastname: Friis
authors.forename: David
authors.initials: D
authors.lastname: Chadwick
authors.forename: Alan
authors.initials: A
authors.lastname: Richens
authors.forename: Athanasios
authors.initials: A
authors.lastname: Covanis
authors.forename: Manuela
authors.initials: M
authors.lastname: Santos
authors.forename: Alexis
authors.initials: A
authors.lastname: Arzimanoglou
authors.forename: Chrysostomos P
authors.initials: CP
authors.lastname: Panayiotopoulos
authors.forename: William P
authors.initials: WP
authors.lastname: Whitehouse
authors.forename: Michele
authors.initials: M
authors.lastname: Rees
authors.forename: R Mark
authors.initials: RM
authors.lastname: Gardiner
mesh_terms: D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor