Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear.
Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.
Aridon
Paolo
P
Human Molecular Genetics Unit, Dibit San Raffaele Scientific Institute, Milan, Italy.
Marini
Carla
C
Di Resta
Chiara
C
Brilli
Elisa
E
De Fusco
Maurizio
M
Politi
Fausta
F
Parrini
Elena
E
Manfredi
Irene
I
Pisano
Tiziana
T
Pruna
Dario
D
Curia
Giulia
G
Cianchetti
Carlo
C
Pasqualetti
Massimo
M
Becchetti
Andrea
A
Guerrini
Renzo
R
Casari
Giorgio
G
D000109:Acetylcholine / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D005239:Fear / Q000523:psychology; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism*; D010375:Pedigree; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology; D013009:Somnambulism / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology
C436489:CHRNA2 protein, human; D008024:Ligands; D011978:Receptors, Nicotinic; D000109:Acetylcholine