Abstracts

Mutation of a Putative Potassium Channel Tetramerization Domain in Familial Progressive Myoclonic Epilepsy

Abstract number : 4.243
Submission category : Human Genetics
Year : 2006
Submission ID : 6486
Source : www.aesnet.org
Presentation date : 12/1/2006 12:00:00 AM
Published date : Nov 30, 2006, 06:00 AM

Authors :
1Patrick Van Bogaert, 2Regis Azizieh, 1Alec Aeby, 3Linda De Meirleir, 4Florence Christiaens, 2Julie Desir, and 2Marc J. Abramowicz

Rare, mendelian forms of epilepsy amenable to positional cloning help understand the molecular mechanisms of epilepsy., Three female patients from two consanguinity loops in a large inbred Morroccan family were investigated for progressive myoclonic epilepsy (PME). After exclusion of known causes, linkage study and analysis of candidate genes were performed., Epilepsy started between 18 and 24 months of age after normal psychomotor development. Seizure types were multifocal myoclonus affecting limbs and face and aggravated by movements, and febrile generalized tonic-clonic in one patient. EEG showed slow dysrythmia, multifocal epileptiform discharges without reproducible temporal relationship with myoclonus and occasional generalized epileptiform discharges. Photosensibility was present in one patient. Giant somatosensory evoked potentials were not found. Cerebral MR imaging and fundoscopy were normal. In 2 patients, seizures were refractory to anti-epileptic drugs. Evolution was unfavourable in both of them: one patient died from septic shock in the course of a corticosteroids trial, and the other one, now aged 9 years, showed progressive dysarthria, dementia and ataxia with lost independent walking at age 7. Epileptic seizures were controlled under lamotrigine and clonazepam in the third patient, now aged 16 years, who presented profound mental retardation and dysarthria without ataxia.
GeneChip analysis of 11K SNPs showed a 15 Mb homozygous haplotype common to the 3 patients. Further analysis using microsatellite markers confirmed linkage of the disease to a 5 cM pericentromeric region of chromosome 7, with a maximum multipoint LOD of 4.2 at D7S663. In silico inspection showed the gene for a Potassium Channel Tetramerization Domain homolog, [italic]KCTD7[/italic], close to D7S663 within the segment. [italic]KCTD7[/italic] contains a BTB/POZ-type domain and has strong homology with the T1 domain of the voltage-gated potassium channels. Direct sequencing of [italic]KCTD7[/italic] revealed a C to T transition creating a stop codon in exon 2, homozygous in patients and heterozygous in parents., PME in our patients was associated with a mutation of the [italic]KCTD7[/italic] gene encoding a putative potassium channel tetramerization domain, consistent with a defect of membrane repolarization.,
Genetics