Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy
Autor: | Maurizio Taglialatela, Anna Guacci, Maria Virginia Soldovieri, Paolo Ambrosino, Gianluca Casara, Marilena Vecchi, Ilaria Mosca, Francesca Rizzo, Laura Manocchio, Giovanna Marchese, Giangennaro Coppola, Teresa Rocco, Massimiliano Chetta, Alessandro Weisz |
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Přispěvatelé: | Rizzo, F, Ambrosino, P, Guacci, A, Chetta, M, Marchese, G, Rocco, T, Soldovieri, Mv, Manocchio, L, Mosca, I, Casara, G, Vecchi, M, Taglialatela, Maurizio, Coppola, G, Weisz, A. |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Potassium Channels Mutant Early-onset epileptic encephalopathies MMPSI Mutation Missense Nerve Tissue Proteins Gating CHO Cells Biology Potassium Channels Sodium-Activated 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cricetulus Cricetinae medicine Potassium Channel Blockers Homomeric Animals Humans Exome Molecular Biology Exome sequencing Genetics Whole-cell electrophysiology KCNT1 gene Whole exome sequencing Infant Cell Biology Molecular biology Potassium channel 030104 developmental biology Bepridil Heterologous expression Ion Channel Gating Spasms Infantile 030217 neurology & neurosurgery medicine.drug |
Popis: | The KCNT1 gene encodes for subunits contributing to the Na(+)-activated K(+) current (KNa), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild-type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3-1000μM) and bepridil (0.03-10μM) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype-tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients. |
Databáze: | OpenAIRE |
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