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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
- Source :
- Neurobiology of disease 34 (2009): 501–510., info:cnr-pdr/source/autori:Miceli F, Soldovieri MV, Lugli L, Bellini G, Ambrosino P, Migliore M, del Giudice EM, Ferrari F, Pascotto A, Taglialatela M./titolo: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./doi:/rivista:Neurobiology of disease/anno:2009/pagina_da:501/pagina_a:510/intervallo_pagine:501–510/volume:34, Neurobiology of Disease, Vol 34, Iss 3, Pp 501-510 (2009)
- Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Male
Benign familial neonatal seizures
DNA Mutational Analysis
neonatal seizures
Action Potentials
Sequence Homology
Gating
medicine.disease_cause
Membrane Potentials
Epilepsy
Cricetinae
Missense mutation
Potassium channel
Voltage-sensing
Kv7 subunit
KCNQ2
KCNQ3
Mutation
Chemistry
Pyramidal Cells
Neurology
Child, Preschool
Cricetulu
Channel gating
Human
Protein subunit
Models, Neurological
Molecular Sequence Data
Mutation, Missense
CHO Cells
Membrane Potential
Potassium channels
lcsh:RC321-571
KCNQ3 Potassium Channel
DNA Mutational Analysi
Kv7 subunits
Cricetulus
medicine
Animals
Humans
KCNQ2 Potassium Channel
Computer Simulation
Amino Acid Sequence
Action Potential
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Neuronal excitability
Animal
Benign familial neonatal seizure
medicine.disease
Molecular biology
Epilepsy, Benign Neonatal
Electrophysiology
CHO Cell
Pyramidal Cell
Neuroscience
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Neurobiology of disease 34 (2009): 501–510., info:cnr-pdr/source/autori:Miceli F, Soldovieri MV, Lugli L, Bellini G, Ambrosino P, Migliore M, del Giudice EM, Ferrari F, Pascotto A, Taglialatela M./titolo: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./doi:/rivista:Neurobiology of disease/anno:2009/pagina_da:501/pagina_a:510/intervallo_pagine:501–510/volume:34, Neurobiology of Disease, Vol 34, Iss 3, Pp 501-510 (2009)
- Accession number :
- edsair.doi.dedup.....6251efcbfedf84218b8428f7a8270876