KCNQ2 mutations cause unique neonatal behavior arrests without motor seizures: Functional characterization

• Published in: Epilepsy & behavior 2024-07, Vol.156, p.109798, Article 109798
• Main Authors: Wong, Swee-Hee, Liou, Ying-Ming, Yang, Jiann-Jou, Lee, Inn-Chi
• Format: Article
• Language: English
• Subjects: Behavior arrest; Functional study; KCNQ2; Neonatal seizures; Phenotype
• ISSN: 1525-5050; 1525-5069; 1525-5069
• DOI: 10.1016/j.yebeh.2024.109798

•KCNQ2 mutations cause distinctive neonatal behavior arrests, autonomic and non-motor seizures with changes in heart rate and respiration.•The KCNQ2 p.Arg448Ter presents non-functional currents; however, after adding wild-type KCNQ2 and KCNQ3, the impaired currents improved and became almost identical to the wild-type.•The homomeric p.Arg448Ter does not express proteins on the cell membrane.•Retigabine opens the heteromeric p.Arg448Ter channel but not the homomeric p.Arg448Ter channel. KCNQ2 gene mutation usually manifests as neonatal seizures in the first week of life. Nonsense mutations cause a unique self-limited familial neonatal epilepsy (SLFNE), which is radically different from developmental epileptic encephalopathy (DEE). However, the exact underlying mechanisms remain unclear. The proband, along with their mother and grandmother, carried the c.1342C > T (p.Arg448Ter) mutation in the KCNQ2 gene. The clinical phenotypes, electroencephalography (EEG) findings, and neurodevelopmental outcomes were comprehensively surveyed. The mutant variants were transfected into HEK293 cells to investigate functional changes. The proband exhibited behavior arrests, autonomic and non-motor neonatal seizures with changes in heart rate and respiration. EEG exhibited focal sharp waves. Seizures were remitted after three months of age. The neurodevelopmental outcomes at three years of age were unremarkable. A functional study demonstrated that the currents of p.Arg448Ter were non-functional in homomeric p.Arg448Ter compared with that of the KCNQ2 wild type. However, the current density and V1/2 exhibited significant improvement and close to that of the wild-type after transfection with heteromeric KCNQ2 + p.Arg448Ter and KCNQ2 + KCNQ3 + p.Arg448Ter respectively. Channel expression on the cell membrane was not visible after homomeric transfection, but not after heteromeric transfection. Retigabine did not affect homomeric p.Arg448Ter but improved heteromeric p. Arg448Ter + KCNQ2 and heteromeric KCNQ2 + Arg448Ter + KCNQ3. The newborn carrying the p. Arg448Ter mutation presented frequent behavioral arrests, autonomic, and non-motor neonatal seizures. This unique pattern differs from KCNQ2 seizures, which typically manifest as motor seizures. Although p.Arg448Ter is a non-sense decay, the functional study demonstrated an almost-full compensation mechanism after transfection of heteromeric KCNQ2 and KCNQ3.