Neutralization of a unique, negatively-charged residue in the voltage sensor of K V 7.2 subunits in a sporadic case of benign familial neonatal seizures.
Benign Familial Neonatal Seizures (BFNS) is a rare, autosomal-dominant epilepsy of the newborn caused by mutations in K(v)7.2 (KCNQ2) or K(v)7.3 (KCNQ3) genes encoding for neuronal potassium (K(+)) channel subunits. In this study, we describe a sporadic case of BFNS; the affected child carried heterozygous missense mutations in both K(v)7.2 (D212G) and K(v)7.3 (P574S) alleles. Electrophysiological experiments revealed that the K(v)7.2 D212G substitution, neutralizing a unique negatively-charged residue in the voltage sensor of K(v)7.2 subunits, altered channel gating, leading to a marked destabilization of the open state, a result consistent with structural analysis of the K(v)7.2 subunit, suggesting a possible pathogenetic role for BFNS of this K(v)7.2 mutation. By contrast, no significant functional changes appeared to be prompted by the K(v)7.3 P574S substitution. Computational modelling experiments in CA1 pyramidal cells revealed that the gating changes introduced by the K(v)7.2 D212G increased cell firing frequency, thereby triggering the neuronal hyperexcitability which underlies the observed neonatal epileptic condition.
Miceli
Francesco
F
Division of Pharmacology, Department of Neuroscience, University of Naples Federico II, Naples, Italy.
Soldovieri
Maria Virginia
MV
Lugli
Licia
L
Bellini
Giulia
G
Ambrosino
Paolo
P
Migliore
Michele
M
del Giudice
Emanuele Miraglia
EM
Ferrari
Fabrizio
F
Pascotto
Antonio
A
Taglialatela
Maurizio
M
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D008959:Models, Neurological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017966:Pyramidal Cells / Q000503:physiopathology; D017385:Sequence Homology
D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel