Wariant kanału potasowego KV3.1 związany z epilepsją działa poprzez efekt dominujący-dodatni
An epilepsy-associated KV3.1 potassium channel variant acts via dominant-positive effect
W skrócie
Naukowcy badali zmianę genetyczną w genie KCNC1, która koduje kanał potasowy KV3.1 mózgu. Odkryli, że ta mutacja powoduje dziwny efekt: sama zmiana nie działa prawidłowo, ale gdy współwystępuje z normalnym kanałem, zmienia sposób jego pracy, co prowadzi do łagodniejszych objawów epilepsji i problemów koordynacji niż inne podobne mutacje. Wyniki sugerują, że ta konkretna zmiana genetyczna zaburza działanie kanałów potasowych w mozgu, wyjaśniając, dlaczego pacjent ma stosunkowo łagodne objawy mimo poważnego defektu genetycznego.
Oryginalny abstract (angielski)
Variants in KCNC1 encoding the voltage-gated potassium (K+) channel subunit KV3.1 are an emerging cause of a spectrum of neurological disease including developmental delay/intellectual disability, ataxia, myoclonus, and epilepsy, including progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Here, we report novel biophysical properties of a recurrent de novo missense variant in KCNC1 c.1196C>T (p.Thr399Met) associated with epilepsy, mild developmental delay, and nonprogressive ataxia. The variant is localized to the highly conserved pore region of the channel, and voltage-clamp electrophysiological recording demonstrated a complete loss of function, as seen in more severe forms of KCNC1-related disorders. When expressed with wild-type (WT) to mimic the heterozygous state of the variant as would occur in a disease context, current density was not markedly reduced; however, resulting currents displayed a ∼20 mV hyperpolarizing shift of the voltage dependence of activation along with slowed deactivation kinetics, consistent with gain of function. In order to better understand this "dominant-positive effect" exerted on the WT channel, we co-expressed the KV3.1 p.Thr399Met variant with the recurrent p.Ala421Val variant known to act via loss of function with near-complete absence of current and associated with severe KCNC1-related disease. Co-expression of the two nonfunctioning variants led to a mild rescue of K+ current compared with the KCNC1-p.Ala421Val variant alone, further supporting a dominant-positive effect. Both KCNC1-p.Thr399Met and p.Ala421Val displayed trafficking deficiency. These results suggest that inclusion of the p.Thr399Met variant in heterotetrameric KV3 channels alters the gating kinetics of WT channel subunits, and highlight the unique features of this variant. The apparent complete loss of function of the p.Thr399Met variant when expressed alone is inconsistent with the relatively mild clinical presentation of the patient, subsequently explained via the "dominant-positive" action when combined with WT subunits.