Abstracts

Rationale: Progressive myoclonus epilepsy is a group of neurological disorders presenting with seizures, myoclonus, ataxia, and gradual neurological decline. One of its forms, recently described as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), is caused by a recurrent de novo mutation in the KCNC1 gene resulting in a single amino acid exchange R320H. KCNC1 encodes the voltage-gated potassium channel Kv3.1, highly expressed in fast spiking interneurons and cerebellum. Expression of the R320H mutation in Xenopus laevis oocytes and CHO cells revealed a loss-of-function with a dominant-negative effect. Therefore, reduced function of inhibitory neurons has been proposed as the possible cause of MEAK. Methods: To further explore the impact of the R320H mutation and the related mechanism in vivo, we generated a knock-in mouse model carrying the corresponding alteration in the Kcnc1 gene. Results: Initial examination revealed that heterozygous Kcnc1RH/+ mice do not show any seizures or other apparent behavioural changes. In contrast, homozygous mice have a shorter life span and are smaller in size than wild type or heterozygous littermates. Electroencephalographic analysis revealed abundant presence of spikes in the Kcnc1RH/RH mice, not observed in Kcnc1RH/+mice. Increased susceptibility to pentylenetetrazol-induced seizures was found for both homo and heterozygous mice, while only the former showed lower threshold for thermally-induced seizures. Conclusions: Overall, these data demonstrate that homozygous mice carrying the KCNC1 R320H mutation recapitulate some aspects of the clinical phenotype of patients with the KCNC1 mutation. Ongoing studies are looking into the cellular and network mechanisms underlying the observed phenotypes. Funding: NHMRC