A MISSENSE MUTATION IN THE NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR ALPHA-4 SUBUNIT IS ASSOCIATED WITH AUTOSOMAL-DOMINANT NOCTURNAL FRONTAL-LOBE EPILEPSY

Epilepsy affects at least 2% of the population at some time in their lives1. The epilepsies are a heterogeneous group of disorders, many with an inherited component2. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder3–4, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes5–7, but only very recently for familial partial epilepsy syndromes8,9. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood10,11. The gene for ADNFLE maps to chromosome 20q13.2–q13.3 in one large Australian kindred8. The neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex13. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects. © 1995 Nature Publishing Group.