Open AccessGain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy
Author(s) -
Mario Nappi,
Vincenzo Barrese,
Lidia Carotenuto,
Gaëtan Lesca,
Audrey Labalme,
Dorothée Ville,
Thomas Smol,
Mélanie Rama,
Anne Dieux-Coëslier,
Clotilde Rivier-Ringenbach,
Maria Virginia Soldovieri,
Paolo Ambrosino,
Ilaria Mosca,
Michael Pusch,
Francesco Miceli,
Maurizio Taglialatela
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2116887119
Subject(s) - potassium channel , electrophysiology , membrane potential , biology , epilepsy , hyperpolarization (physics) , biophysics , protein subunit , neuroscience , mutation , microbiology and biotechnology , genetics , chemistry , gene , organic chemistry , nuclear magnetic resonance spectroscopy
Significance Variants in genes encoding neuronally expressed potassium channel subunits are frequent causes of developmental and epileptic encephalopathies (DEEs). Characterization of their functional consequences is critical to confirm diagnosis, assess prognosis, and implement personalized treatments. In the present work, we describe two patients carrying variants inKCNQ5 , a gene very recently and rarely found involved in DEEs, and reveal that they both cause remarkable gain-of-function consequences on channel activity. A PIP2 -independent increase in open probability, without effects on membrane abundance or single-channel conductance, was responsible for the observed mutation-induced functional changes, thus revealing a pathomolecular disease mechanism for DEEs.