title: Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.
abstract: Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
authors.affiliation: Department of Medicine and Health Science, University of Molise, Campobasso, Italy.
authors.forename: Maria Virginia
authors.initials: MV
authors.lastname: Soldovieri
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutry-Kryza
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.forename: Benedicte
authors.initials: B
authors.lastname: Heron
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourel
authors.forename: Paolo
authors.initials: P
authors.lastname: Ambrosino
authors.forename: Francesco
authors.initials: F
authors.lastname: Miceli
authors.forename: Michela
authors.initials: M
authors.lastname: De Maria
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dorison
authors.forename: Stephane
authors.initials: S
authors.lastname: Auvin
authors.forename: Bernard
authors.initials: B
authors.lastname: Echenne
authors.forename: Julie
authors.initials: J
authors.lastname: Oertel
authors.forename: Audrey
authors.initials: A
authors.lastname: Riquet
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lambert
authors.forename: Marion
authors.initials: M
authors.lastname: Gerard
authors.forename: Anne
authors.initials: A
authors.lastname: Roubergue
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
mesh_terms: D000818:Animals; D019921:Biotinylation; D016466:CHO Cells; D015331:Cohort Studies; D003412:Cricetulus; D020936:Epilepsy, Benign Neonatal / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D051659:KCNQ3 Potassium Channel / Q000235:genetics*; D008297:Male; D016254:Mutagenesis, Insertional; D010375:Pedigree; D016415:Sequence Alignment; D050827:Syntaxin 1 / Q000235:genetics*
chemical_list: D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D050827:Syntaxin 1
keywords: KCNQ2; KCNQ3; benign; familial; neonatal epilepsy; syntaxin-1A; voltage-gated potassium channels