Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca(2+) channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Ca(v)2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca(2+) currents that were reversed by the mutations associated with JME.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases.1,2 Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity.3-5 Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups.6-8 In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues 9 found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 10 among ADHD subjects compared to controls. Swanson and colleagues 11 replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT)12 and a mean test of identity-bydescent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.13