A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy

Epilepsia. 2003 Jul;44(7):981-5. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence / genetics
  • Animals
  • Anticonvulsants / therapeutic use
  • Carbamazepine / therapeutic use
  • Child
  • Epilepsy, Frontal Lobe / diagnosis
  • Epilepsy, Frontal Lobe / genetics*
  • Female
  • Gene Expression / physiology
  • Genetic Carrier Screening
  • Humans
  • Isoleucine / genetics
  • Male
  • Middle Aged
  • Oocytes
  • Pedigree
  • Penetrance*
  • Phenotype
  • Polymerase Chain Reaction
  • Receptors, Nicotinic / genetics*
  • Sleep Wake Disorders / diagnosis
  • Sleep Wake Disorders / genetics*
  • Threonine / genetics
  • Xenopus


  • Anticonvulsants
  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit
  • Isoleucine
  • Threonine
  • Carbamazepine