title: Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families.
abstract: OBJECTIVE
  The EFHC1 gene, encoding a protein with a Ca(2+)-sensing EF-hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families linked to this region. We had previously confirmed linkage between JME and 6p11-12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11-12-linked families.
  
  
  METHODS
  We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case-control association study.
  
  
  RESULTS
  We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5' upstream region (c.-146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3' UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11-12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients.
  
  
  CONCLUSIONS
  We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11-12 is yet to be identified.
authors.affiliation: Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: Sandrien
authors.initials: S
authors.lastname: Louwaars
authors.forename: Birgit
authors.initials: B
authors.lastname: Westland
authors.forename: Linda
authors.initials: L
authors.lastname: Volkers
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: de Haan
authors.forename: Dorothée G A Kasteleijn-Nolst
authors.initials: DG
authors.lastname: Trenité
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005190:Family; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008800:Mexico; D009154:Mutation / Q000235:genetics*; D020190:Myoclonic Epilepsy, Juvenile / Q000453:epidemiology / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D012307:Risk Factors; D044465:White People
chemical_list: D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human; D005819:Genetic Markers