title: Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC).
abstract: Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in KCNQ2 and KCNQ3, two genes encoding for potassium channel subunits. A large family with nine members affected by BFNC is described in the present study. All affected members of this family carry a novel deletion/insertion mutation in the KCNQ2 gene (c.761_770del10insA), which determines a premature truncation of the protein. In addition, in the family of the proposita's father, a novel sequence variant (c.2687A>G) in KCNQ3 leading to the p.N821S amino acid change was detected. When heterologously expressed in Chinese hamster ovary cells, KCNQ2 subunits carrying the mutation failed to form functional potassium channels in homomeric configuration and did not affect channels formed by KCNQ2 and/or KCNQ3 subunits. On the other hand, homomeric and heteromeric potassium channels formed by KCNQ3 subunits carrying the p.N821S variant were indistinguishable from those formed by wild-type KCNQ3 subunits. Finally, the current density of the cells mimicking the double heterozygotic condition for both KCNQ2 and KCNQ3 alleles of the proband was decreased by approximately 25% when compared to cells expressing only wild-type alleles. Collectively, these results suggest that, in the family investigated, the KCNQ2 mutation is responsible for the BFNC phenotype, possibly because of haplo-insufficiency, whereas the KCNQ3 variant is functionally silent, a result compatible with its lack of segregation with the BFNC phenotype.
authors.affiliation: IRCCS E. Medea, Via D.L. Monza 20, 23842 Bosisio Parini Lecco, Italy. mtbassi@bp.lnf.it
authors.forename: Maria T
authors.initials: MT
authors.lastname: Bassi
authors.forename: Umberto
authors.initials: U
authors.lastname: Balottin
authors.forename: Chris
authors.initials: C
authors.lastname: Panzeri
authors.forename: Paolo
authors.initials: P
authors.lastname: Piccinelli
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Castaldo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barrese
authors.forename: Maria V
authors.initials: MV
authors.lastname: Soldovieri
authors.forename: Francesco
authors.initials: F
authors.lastname: Miceli
authors.forename: Maria
authors.initials: M
authors.lastname: Colombo
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Renato
authors.initials: R
authors.lastname: Borgatti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D020936:Epilepsy, Benign Neonatal / Q000235:genetics*; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D051659:KCNQ3 Potassium Channel / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel