Maljevic S et al. (2016), Novel KCNQ3 Mutation in a Large Family with Ben...

XB-ART-52669

Mol Syndromol 2016 Sep 01;74:189-196. doi: 10.1159/000447461.

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Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures.

Maljevic S , Vejzovic S , Bernhard MK , Bertsche A , Weise S , Döcker M , Lerche H , Lemke JR , Merkenschlager A , Syrbe S .

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Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, c.835G>T, cosegregating with seizures in 4 tested individuals. This variant results in a substitution of the highly conserved amino acid valine localized within the pore-forming transmembrane segment S5 (p.V279F). Functional investigations in Xenopus laevis oocytes revealed a loss of function, which supports p.V279F as a pathogenic mutation. When p.V279F was coexpressed with the wild-type (WT) Kv7.2 subunits, the resulting potassium currents were about 10-fold reduced compared to the WT Kv7.3 and Kv7.2 coexpression. Genotype-phenotype correlation shows an incomplete penetrance of p.V279F. Response to antiepileptic treatment was variable, but evaluation of treatment response remained challenging due to the self-limiting character of the disease. The identification of the pathogenic variant helped to avoid unnecessary investigations in affected family members and allowed guided therapy.

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???displayArticle.pmcLink??? PMC5073621
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Species referenced: Xenopus laevis
Genes referenced: kcnq2 kcnq3
GO keywords: potassium channel activity

???displayArticle.disOnts??? benign familial neonatal epilepsy
???displayArticle.omims??? SEIZURES, BENIGN FAMILIAL NEONATAL, 1; BFNS1 [+]
References [+] :

Biervert, A potassium channel mutation in neonatal human epilepsy. 1998, Pubmed, Xenbase

Biervert, A potassium channel mutation in neonatal human epilepsy. 1998, Pubmed , Xenbase
Charlier, A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. 1998, Pubmed
Maljevic, Potassium channel genes and benign familial neonatal epilepsy. 2014, Pubmed
Miceli, A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. 2015, Pubmed
Miceli, Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. 2015, Pubmed
Neubauer, KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes. 2008, Pubmed , Xenbase
Orhan, Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. 2014, Pubmed , Xenbase
Rundfeldt, The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits. 2000, Pubmed
Singh, Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. 2008, Pubmed
Singh, KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. 2003, Pubmed , Xenbase
Singh, A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. 1998, Pubmed
Soldovieri, 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. 2014, Pubmed
Sugiura, Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC). 2009, Pubmed
Tzingounis, Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents. 2008, Pubmed
Uehara, Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy. 2008, Pubmed
Weckhuysen, Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. 2013, Pubmed
Wuttke, Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. 2007, Pubmed , Xenbase
Zara, Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. 2013, Pubmed