title: A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurology, University of Essen, Essen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Leniger
authors.forename: Colette
authors.initials: C
authors.lastname: Kananura
authors.forename: Andreas
authors.initials: A
authors.lastname: Hufnagel
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Ortrud K
authors.initials: OK
authors.lastname: Steinlein
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D002220:Carbamazepine / Q000627:therapeutic use; D002648:Child; D017034:Epilepsy, Frontal Lobe / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006580:Genetic Carrier Screening; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009865:Oocytes; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011978:Receptors, Nicotinic / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000175:diagnosis / Q000235:genetics*; D013912:Threonine / Q000235:genetics; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D007532:Isoleucine; D011978:Receptors, Nicotinic; D013912:Threonine