Nappi, Mario Gain of Function Effect Caused by Inner Pore Variants in Kv7.2, Kv7.3 and Kv7.5 Potassium Channels Identified in Patients with Developmental and/or Epileptic Encephalopathy. [Tesi di dottorato]

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Abstract

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by seizures, electroencephalographic abnormalities or developmental delay or regression. DEEs have often a genetic etiology and KCNQ are among the most frequently affected genes. these encodes for a family of voltage gated potassium channel subunit and consists of five members (KCNQ1-5). In the present work, we describe the clinical and in vitro functional features of six patients each carrying a heterozygous de novo mutation in KCNQ2, KCNQ3 or KCNQ5, responsible for introducing substitutions in the activation gate of the pore region. We characterise the biophysical properties of these variants and classify them as gain- or loss-of-function variants. We also describe the structural alterations that these mutations induce through molecular dynamics. Finally, we tested 10 micromolar amitriptyline to evaluate the ability of the compound to reverse the in vitro phenotype, showing that this drug is able to reverse the current density of channels. Functional characterisations of de novo variants are crucial to understand pathogenesis of DEEs, to guide therapy and to implement personalised treatments.

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