: SignificanceVariants 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 in KCNQ5, 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.

Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy

Soldovieri, Maria Virginia;Ambrosino, Paolo;Mosca, Ilaria;Taglialatela, Maurizio
2022

Abstract

: SignificanceVariants 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 in KCNQ5, 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11695/107046
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