AN INSERTION MUTATION OF THE CHRNA4 GENE IN A FAMILY WITH AUTOSOMAL-DOMINANT NOCTURNAL FRONTAL-LOBE EPILEPSY

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the fir st, and to date only, idiopathic epilepsy for which a specific mutatio n has been found, A missense mutation in the critical M2 domain of the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (CHR NA4) has been recently identified in one large Australian pedigree. He re we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family Three nucleotides (GCT) were inserted at nucleotid e position 776 into the coding region for the C-terminal end of the M2 domain, Physiological investigations of the receptor reconstituted wi th the mutated CHRNA4 subunit reveal that this insertion does not prev ent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function, Comparison of the two mutations identified so far in famili es with ADNFLE illustrates that different mutations can result in simi lar phenotypes.