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A New Chrna4 Mutation with Low Penetrance in Nocturnal Frontal Lobe Epilepsy
Author(s) -
Leniger Tobias,
Kananura Colette,
Hufnagel Andreas,
Bertrand Sonia,
Bertrand Daniel,
Steinlein Ortrud K.
Publication year - 2003
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2003.61102.x
Subject(s) - penetrance , genetics , transmembrane domain , biology , missense mutation , mutation , epilepsy , nicotinic acetylcholine receptor , locus (genetics) , allele , phenotype , nicotinic agonist , gene , receptor , neuroscience
Summary: Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. Methods: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. Results: We report a new CHRNA4 mutation, causing a α4‐T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of α4‐T265I revealed an increased ACh sensitivity of the mutated receptors. α4‐T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1‐TM3 parts of the 1 known nAChR subunits did not support a two‐locus model involving a second nAChR sequence variation. Conclusions: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. α4‐T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both.