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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• KCNQ2 gene mutations are a common cause of neonatal seizures, often leading to severe developmental epileptic encephalopathy (DEE).
• Nonsense mutations in KCNQ2 can result in a distinct, self-limited familial neonatal epilepsy (SLFNE) with unclear underlying mechanisms.

Purpose of the Study:

• To investigate the clinical presentation and underlying mechanisms of a specific KCNQ2 nonsense mutation (p.Arg448Ter) associated with SLFNE.
• To explore the functional consequences of the p.Arg448Ter mutation on KCNQ2 channel function and potential compensation mechanisms.

Main Methods:

• Clinical phenotyping, electroencephalography (EEG), and neurodevelopmental outcome assessment of a proband and family members with the KCNQ2 c.1342C>T (p.Arg448Ter) mutation.
• In vitro functional studies involving transfection of wild-type and mutant KCNQ2 variants into HEK293 cells to assess channel function, expression, and response to retigabine.

Main Results:

• The proband presented with unique non-motor neonatal seizures (behavioral arrests, autonomic changes) that remitted by three months of age, with normal neurodevelopmental outcomes at three years.
• In vitro, homomeric p.Arg448Ter channels were non-functional, but heteromeric co-expression with wild-type KCNQ2 or KCNQ2/KCNQ3 restored channel function and surface expression.
• Retigabine partially rescued the function of heteromeric channels containing p.Arg448Ter but did not affect homomeric mutant channels.

Conclusions:

• The p.Arg448Ter KCNQ2 mutation causes a distinct neonatal seizure phenotype characterized by non-motor seizures, differing from typical KCNQ2-related DEE.
• Despite being a nonsense mutation, heteromeric interactions with wild-type KCNQ2 and KCNQ3 subunits provide a significant compensation mechanism, explaining the self-limited nature of the epilepsy.