title: An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.
abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent 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 families with ADNFLE illustrates that different mutations can result in similar phenotypes.
authors.affiliation: Institute for Human Genetics, University of Bonn, Germany. human@snphysio2.wilhelm.uni-bonn.de
authors.forename: O K
authors.initials: OK
authors.lastname: Steinlein
authors.forename: A
authors.initials: A
authors.lastname: Magnusson
authors.forename: J
authors.initials: J
authors.lastname: Stoodt
authors.forename: S
authors.initials: S
authors.lastname: Bertrand
authors.forename: S
authors.initials: S
authors.lastname: Weiland
authors.forename: S F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: K O
authors.initials: KO
authors.lastname: Nakken
authors.forename: P
authors.initials: P
authors.lastname: Propping
authors.forename: D
authors.initials: D
authors.lastname: Bertrand
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium; D002463:Cell Membrane Permeability; D018076:DNA, Complementary; D017034:Epilepsy, Frontal Lobe / Q000235:genetics*; D005190:Family; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007930:Leucine; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010375:Pedigree; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: D002118:Calcium; D018076:DNA, Complementary; D007930:Leucine; D011978:Receptors, Nicotinic