Ion channel variation causes epilepsies

The discovery of genetically transmissible form of epilepsy associated with a mutation in a gene that codes for a subunit of a ligand-gated channel sh ined a new light in this field of neurological diseases. Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, fun ctional studies could be designed to evaluate the alterations caused by thi s mutation. Since this initial observation, five mutations were identified and determination of their functional properties initiated. These experimen ts were extended to pairwise expression of the control and mutated allele t o mimic the heterozygote human genotype. The first common functional trait identified so far, in four of these mutants, is an increased sensitivity to the acetylcholine, suggesting that these mutations may cause a gain of fun ction. An alternative possibility that cannot be excluded is that condition s in the brain are such that these higher responding receptors may be more prone to desensitization. The importance of ionic channels as cause of epil epsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for pota ssium channel subunits (KCNQ2, KCNQ3). Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1 A, SCN1B) in a form of generalized epilepsy with febrile seizures. (C) 2001 Elsevier Science BY All rights reserved.