6533b829fe1ef96bd128ae2a
RESEARCH PRODUCT
Increased sensitivity of the neuronal nicotinic receptor alpha-2 subunit causes familial epilepsy with nocturnal wandering and ictal fear
Giorgio CasariCarla MariniFausta PolitiPaolo AridonIrene ManfrediAndrea BecchettiElena ParriniDario PrunaCarlo CianchettiElisa BrilliGiulia CuriaMassimo PasqualettiTiziana PisanoChiara Di RestaMaurizio De FuscoRenzo Guerrinisubject
AdultMalemedicine.medical_specialtyAdolescentSomnambulismMolecular Sequence DataMutation MissenseAutosomal dominant nocturnal frontal lobe epilepsyReceptors NicotinicBiologymedicine.disease_causeLigandsNicotinicArticleEpilepsyBIO/09 - FISIOLOGIAInternal medicineAcetylcholine; Adolescent; Adult; Aged; Aged 80 and over; Amino Acid Sequence; Epilepsy; Female; Humans; Ligands; Male; Molecular Sequence Data; Mutation Missense; Neurons; Pedigree; Receptors Nicotinic; Somnambulism; FearReceptorsmedicine80 and overGeneticsHumansIctalGenetics(clinical)Amino Acid SequenceGenetics (clinical)Acetylcholine receptorAgedAged 80 and overNeuronsMutationEpilepsySeizure typesFearmedicine.diseaseAcetylcholinePedigreeNicotinic acetylcholine receptorNicotinic agonistEndocrinologyMutationnAChR patch-clamp ADNFLE sleep-related epilepsy M1 TM1 ACh nicotineSettore MED/26 - NeurologiaFemaleMissensedescription
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 α4 and β2 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 α2 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 α2 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. © 2006 by The American Society of Human Genetics. All rights reserved.
year | journal | country | edition | language |
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2006-08-01 |