Nicotinic acetylcholine receptor mutations

Excerpt

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first idiopathic epilepsy in humans for which a causative gene defect could be identified. This rare genetic syndrome can be caused by mutations in at least two different subunits genes of the neuronal nicotinic acetylcholine receptor (nAChR), CHRNA4 and CHRNB2. First described in 1995, ADNFLE is characterized by clusters of brief motor seizures that occur mostly during non-REM sleep. It usually starts within the second decade of life but intra- as well as interfamilial variability of the phenotype is considerable. All but one of the known ADNFLE mutations were found either in the second or third transmembrane domain, which count only for a small part of the channel subunits but are functionally crucial for the ion pore. The clustering of the mutations and the repeated occurrence of some of these mutations in different countries suggest that within each subunit only a few amino acid residues are able to cause this type of epilepsy. In vitro expression studies showed that all mutations increase the receptors sensitivity towards acetylcholine, suggesting that a gain-of-function is the basic mechanism behind ADNFLE. However, the extent of the gain-of-function effect varies between mutations, and the mutated nAChRs display individual pathofunctional profiles for agonists such as nicotine or antiepileptic drugs like carbamazepine. It is therefore not surprising that the clinical phenotypes associated with the mutations are not uniform. ADNFLE mutations can be roughly divided into two types, one that in most patients causes only epilepsy and one that seems often to result in epilepsy accompanied by additional neurological features such as psychiatric symptoms, mental retardation or cognitive deficits.