: 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
Ambrosino, Paolo;
2022-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
