Article

Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC)

Department of Neurology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
Epilepsy research (Impact Factor: 2.19). 02/2009; 84(1):82-5. DOI: 10.1016/j.eplepsyres.2008.12.003
Source: PubMed

ABSTRACT BFNC is an autosomal dominant epileptic disorder caused by mutations of KCNQ2 or KCNQ3 potassium channel gene. W309R missense mutation in KCNQ3 gene was previously reported in a family with BFNC. In this study, potassium currents were recorded from HEK293 cells expressing both W309R mutant KCNQ3 and wild type KCNQ2 channels. We found a lack of potassium current in W309R mutant KCNQ3 and KCNQ2 channels, which can explain the hyper-excitability of CNS in patients with BFNC.

Download full-text

Full-text

Available from: Shinichi Hirose, Aug 18, 2015
0 Followers
 · 
170 Views
  • Source
    • "All missense mutations and functional consequences have been studied for five of them; four of them (p.Glu299Lys, p.Asp305Gly, p.Trp309Arg, and p.Gly310Val) are located in the pore region of Q3 and the fifth one (p.Arg330Cys) immediately before S6. Functional analyses in Xenopus oocytes showed that Q3 subunits carrying the p.Gly310Val and p.Asp305Gly mutation caused a 20% and 40% reduction, respectively , in the maximal current of heteromeric Q2/Q3 channels [Schroeder et al., 1998; Singh et al., 2003], whereas the Q3 p.Trp309Arg mutation was found to reduce by over 60% the Q2/Q3 heteromeric channel currents in HEK293 cells, suggesting a dominant negative effect [Uehara et al., 2008; Sugiura et al., 2009]. "
    [Show abstract] [Hide abstract]
    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, EEG suppression-burst pattern (Ohtahara syndrome) and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy". In the present paper, we describe clinical, genetic and functional data from 17 patients/families whose electro-clinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three ins/del 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. This article is protected by copyright. All rights reserved.
    Human Mutation 12/2013; 35(3). DOI:10.1002/humu.22500 · 5.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: KCNQ3-related disorders discussed in this GeneReview are benign familial neonatal epilepsy (BFNE) and benign familial infantile epilepsy (BFIE), seizure disorders that occur in children who have normal psychomotor development. In BFNE seizures begin in an otherwise healthy infant between days two and eight of life and spontaneously disappear between the first and the sixth to 12th month of life. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes, focal clonic activity, and autonomic changes. Motor activity may be confined to one body part, migrate to other regions, or generalize. Infants are well between seizures and feed normally. In BFIE seizures begin about age six months (range 3-8 months) and disappear about age two years. Seizures are generally brief, lasting two minutes; they appear as daily repeated clusters. Seizure type is usually focal, but can be also generalized, causing diffuse hypertonia with jerks of the limbs, head deviation, or motor arrest with unconsciousness and cyanosis.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epilepsy syndromes denote specific constellations of clinical seizure type(s), EEG findings, and other characteristic clinical features. Most syndromes recognized in epilepsy are genetic and developmental disorders that begin in the pediatric years. Epilepsy syndromes are divided into idiopathic (primary) types, in which the presumed etiology is genetic, versus symptomatic (secondary) types, in which there is either an underlying etiology that is known or presumed based on other evidence of brain dysfunction. Epilepsies are also classified by those with generalized seizures and those with localization-related seizures. Identification of a specific syndrome is important to define the best treatment and accurately prognosticate long-term outcome for children with epilepsy. In this chapter, clinical and electrographic features as well as inheritance patterns of common pediatric epilepsy syndromes are discussed.
    CONTINUUM Lifelong Learning in Neurology 06/2010; 16(3 Epilepsy):57-85. DOI:10.1212/01.CON.0000368232.19116.3d
Show more