How mutations in the nAChRs can cause ADNFLE epilepsy

Epilepsia. 2002;43 Suppl 5:112-22. doi: 10.1046/j.1528-1157.43.s.5.16.x.


Purpose: The linkage between autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and neuronal nicotinic acetylcholine receptor has been strongly reinforced by the report of five distinct mutations in the two genes coding for the major brain alpha4beta2 nicotinic acetylcholine (ACh) receptors. As a first step toward understanding the basic mechanisms underlying this genetically transmissible neurologic disorder, we examined the similarities and differences of the functional properties displayed by naturally occurring mutant forms of this ligand-gated channel.

Methods: Functional studies of neuronal nicotinic ACh receptors reconstituted in Xenopus oocytes were designed to analyze the common traits displayed by the different mutations associated with ADNFLE.

Results: Coexpression of the control and mutated alleles harboring the alpha4S248F mutation obtained from patient DNAs yielded ACh-evoked currents of amplitude comparable to the control responses but with a higher sensitivity and desensitization to the natural agonist. Alternatively, the other mutants (alpha4L776ins3, alpha4S252L, and beta2V287M) displayed an increased ACh sensitivity without pronounced desensitization. In addition, whereas a reduction of calcium permeability was observed for the mutants (alpha4S248F and alpha4L776ins3), no significant modification of ionic selectivity could be detected in the alpha4S252L mutation. Hence increase in ACh sensitivity is the only common characteristic so far observed between the four naturally occurring mutant receptors investigated.

Conclusions: Analyses of functional properties of four nAChR mutants associated with ADNFLE indicate that a gain of function of these mutant receptors may be at the origin of the neuronal network dysfunction that causes the epileptic seizures. These data are discussed in the context of our latest knowledge of the pyramidal cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Alleles
  • Animals
  • Circadian Rhythm*
  • Electric Conductivity
  • Epilepsy, Temporal Lobe / genetics*
  • Epilepsy, Temporal Lobe / physiopathology*
  • Genes, Dominant*
  • Humans
  • Mutation / physiology*
  • Nerve Net / physiopathology
  • Oocytes
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / genetics*
  • Receptors, Nicotinic / metabolism
  • Xenopus


  • CHRNA2 protein, human
  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit
  • Acetylcholine