Valerio Conti1, Patrizia Aracri1, Laura Chiti1, Simone Brusco1, Francesco Mari1, Carla Marini1, Maria Albanese1, Angela Marchi1, Claudio Liguori1, Fabio Placidi1, Andrea Romigi1, Andrea Becchetti1, Renzo Guerrini2. 1. From the Pediatric Neurology and Neurogenetics Unit and Laboratories (V.C., L.C., F.M., C.M., R.G.), A. Meyer Children's Hospital-University of Florence; Department of Biotechnology and Biosciences and Center of Neuroscience (P.A., S.B., A.B.), Università di Milano-Bicocca, Milan; Neurophysiopathology Unit (M.A., A.M., C.L., F.P., A.R.), Sleep and Epilepsy Center, Department of Systems Medicine, University of Rome Tor Vergata General Hospital, Rome; IRCCS Neuromed (A.R.), Pozzilli, Isernia; and IRCCS Stella Maris Foundation (R.G.), Calambrone, Pisa, Italy. 2. From the Pediatric Neurology and Neurogenetics Unit and Laboratories (V.C., L.C., F.M., C.M., R.G.), A. Meyer Children's Hospital-University of Florence; Department of Biotechnology and Biosciences and Center of Neuroscience (P.A., S.B., A.B.), Università di Milano-Bicocca, Milan; Neurophysiopathology Unit (M.A., A.M., C.L., F.P., A.R.), Sleep and Epilepsy Center, Department of Systems Medicine, University of Rome Tor Vergata General Hospital, Rome; IRCCS Neuromed (A.R.), Pozzilli, Isernia; and IRCCS Stella Maris Foundation (R.G.), Calambrone, Pisa, Italy. r.guerrini@meyer.it.
Abstract
OBJECTIVE: We assessed the mutation frequency in nicotinic acetylcholine receptor (nAChR) subunits CHRNA4, CHRNB2, and CHRNA2 in a cohort including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and sporadic nocturnal frontal lobe epilepsy (NFLE). Upon finding a novel mutation in CHRNA2 in a large family, we tested in vitro its functional effects. METHODS: We sequenced all the coding exons and their flanking intronic regions in 150 probands (73 NFLE, 77 ADNFLE), in most of whom diagnosis had been validated by EEG recording of seizures. Upon finding a missense mutation in CHRNA2, we measured whole-cell currents in human embryonic kidney cells in both wild-type and mutant α2β4 and α2β2 nAChR subtypes stimulated with nicotine. RESULTS: We found a c.889A>T (p.Ile297Phe) mutation in the proband (≈0.6% of the whole cohort) of a large ADNFLE family (1.2% of familial cases) and confirmed its segregation in all 6 living affected individuals. Video-EEG studies demonstrated sleep-related paroxysmal epileptic arousals in all mutation carriers. Oxcarbazepine treatment was effective in all. Whole-cell current density was reduced to about 40% in heterozygosity and to 0% in homozygosity, with minor effects on channel permeability and sensitivity to nicotine. CONCLUSION: ADNFLE had previously been associated with CHRNA2 dysfunction in one family, in which a gain of function mutation was demonstrated. We confirm the causative role of CHRNA2 mutations in ADNFLE and demonstrate that also loss of function of α2 nAChRs may have pathogenic effects. CHRNA2 mutations are a rare cause of ADNFLE but this gene should be included in mutation screening.
OBJECTIVE: We assessed the mutation frequency in nicotinic acetylcholine receptor (nAChR) subunits CHRNA4, CHRNB2, and CHRNA2 in a cohort including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and sporadic nocturnal frontal lobe epilepsy (NFLE). Upon finding a novel mutation in CHRNA2 in a large family, we tested in vitro its functional effects. METHODS: We sequenced all the coding exons and their flanking intronic regions in 150 probands (73 NFLE, 77 ADNFLE), in most of whom diagnosis had been validated by EEG recording of seizures. Upon finding a missense mutation in CHRNA2, we measured whole-cell currents in human embryonic kidney cells in both wild-type and mutant α2β4 and α2β2 nAChR subtypes stimulated with nicotine. RESULTS: We found a c.889A>T (p.Ile297Phe) mutation in the proband (≈0.6% of the whole cohort) of a large ADNFLE family (1.2% of familial cases) and confirmed its segregation in all 6 living affected individuals. Video-EEG studies demonstrated sleep-related paroxysmal epileptic arousals in all mutation carriers. Oxcarbazepine treatment was effective in all. Whole-cell current density was reduced to about 40% in heterozygosity and to 0% in homozygosity, with minor effects on channel permeability and sensitivity to nicotine. CONCLUSION: ADNFLE had previously been associated with CHRNA2 dysfunction in one family, in which a gain of function mutation was demonstrated. We confirm the causative role of CHRNA2 mutations in ADNFLE and demonstrate that also loss of function of α2 nAChRs may have pathogenic effects. CHRNA2 mutations are a rare cause of ADNFLE but this gene should be included in mutation screening.
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