A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.
paper
Cited
Public
Unavailable
- Authors
- Leniger, Tobias; Kananura, Colette; Hufnagel, Andreas; Bertrand, Sonia; Bertrand, Daniel; Steinlein, Ortrud K
- Year
- 2003
- Journal
- Epilepsia
- PMID
- 12823585
- DOI
- 10.1046/j.1528-1157.2003.61102.x
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 alpha4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of alpha4-T265I revealed an increased ACh sensitivity of the mutated receptors. alpha4-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. alpha4-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.
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