Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 72, Issue -, Pages 54-63Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2016.01.004
Keywords
Early-onset epileptic encephalopathies; MMPSI; KCNT1 gene; Whole exome sequencing; Whole-cell electrophysiology
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Funding
- Italian Ministry for Education, University and Research [BIBIOFAR PON03PE_00146_1]
- National Research Council of Italy (Flagship Project InterOmics)
- University of Salerno [FARB 2014-15]
- Fondazione 'Umberto Veronesi'
- Telethon [GGP15113]
- Genomix4Life Srl
- Italian Society for Pharmacology
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The KCNT1 gene encodes for subunits contributing to the Na+-activated K+ current (K-Na), 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 (3-1000 mu M) and bepridil (0.03-10 mu M) 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. (C) 2016 Published by Elsevier Inc.
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