Ciężka epilepsja noworodka związana z nową mutacją genu SLC12A5 powodującą zaburzenie transportu chloru
Severe neonatal epilepsy linked to a novel homozygous SLC12A5 Arg508Cys variant with impaired chloride transport
W skrócie
Naukowcy odkryli nowy rodzaj mutacji genu SLC12A5 u noworodka z bardzo ciężką epilepsją, która nie reagowała na leki. Gen ten odpowiada za białko KCC2, które reguluje ilość chloru w komórkach mózgu i jest niezbędne do prawidłowego funkcjonowania obwodów nerwowych, które hamują napady padaczki. Badania wykazały, że ta mutacja powoduje, iż białko KCC2 nie pracuje prawidłowo - chlor gromadzi się w komórkach nerwowych, co prowadzi do nadmiernej ich pobudliwości i napadów padaczki.
Oryginalny abstract (angielski)
The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABA receptors produces hyperpolarizing inhibitory responses rather than depolarizing responses. Disruption of KCC2 function can therefore impair GABAergic signaling and neuronal maturation, contributing to a range of neurodevelopmental and neurological disorders. Pathogenic biallelic variants in SLC12A5, the gene encoding KCC2, are a rare cause of severe early-onset developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). Here, we describe a novel homozygous SLC12A5 variant identified in a patient with severe, drug-resistant epilepsy, neonatal encephalopathy, and rapid neurological deterioration. Combined Western blot, thallium (Tl) flux, and gramicidin-perforated patch-clamp assays revealed significantly reduced ion-transport function of the KCC2 construct encoding the variant, with no change in protein expression abundance or profile. Live-cell surface immunolabeling demonstrated markedly reduced plasma membrane expression and decreased internalization of the variant, suggesting that the functional deficit primarily results from defective trafficking or reduced membrane stability. These findings expand the spectrum of KCC2-related disorders and highlight the critical role of KCC2 in early brain development. By linking a specific SLC12A5 variant to impaired chloride homeostasis and neuronal hyperexcitability, this study provides mechanistic insight into disease pathogenesis and lays the groundwork for therapeutic strategies aimed at restoring or stabilizing KCC2 function.