Article
Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.
Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
The American Journal of Human Genetics (impact factor:
10.6).
05/2007;
80(4):792-9.
DOI:10.1086/513019
pp.792-9
Source: PubMed
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Article: Mutations in EFHC1 cause juvenile myoclonic epilepsy.
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ABSTRACT: 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.Nature Genetics 09/2004; 36(8):842-9. · 35.53 Impact Factor
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Keywords
2q37 breakpoint
abnormal epileptic discharges
capillary abnormality
central nervous system development
de novo balanced translocation
developmental delay
Dgkd mutant mice
diacylglycerol kinase delta
Electroencephalographic assessment
electrographic seizures
exhibits seizures
Expression studies
female patient
findings implicate DGKD disruption
general role
infantile hypotonia
particular interest
seizure phenotype
situ hybridization
translocation breakpoints
