A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.
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.
Leniger
Tobias
T
Department of Neurology, University of Essen, Essen, Germany.
Kananura
Colette
C
Hufnagel
Andreas
A
Bertrand
Sonia
S
Bertrand
Daniel
D
Steinlein
Ortrud K
OK
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
D000927:Anticonvulsants; D002220:Carbamazepine; D007532:Isoleucine; D011978:Receptors, Nicotinic; D013912:Threonine