Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in Kv7.2 and Kv7.3 potassium channels are associated with various seizure disorders.
• Characterizing newly identified variants is crucial for linking genotype to phenotype in epilepsy.

Purpose of the Study:

• To identify and functionally characterize a novel mutation, Kv7.3[T313I], in the selectivity filter of Kv7.3.
• To investigate the impact of this mutation on Kv7.3 channel function and its role in neonatal seizures.

Main Methods:

• Next-generation sequencing identified the Kv7.3[T313I] mutation in a family with neonatal seizures.
• Electrophysiological studies in *Xenopus laevis* oocytes assessed the functional consequences of the mutation.

Main Results:

• The T313I substitution disrupts a critical intersubunit hydrogen bond, leading to a complete loss of function in homomeric Kv7.3 channels.
• In heteromeric channels with Kv7.2, Kv7.3[T313I] caused modest current suppression, but functional channels were still formed, especially with Kv7 activators.
• Assembly of Kv7.2 and Kv7.3[T313I] generates functional channels, indicating a complex impact on channel activity.

Conclusions:

• The biophysical and clinical effects of the T313I mutation align with previously identified Kv7.3 mutations in self-limiting neonatal epilepsy.
• These findings contribute to the growing list of functionally characterized Kv7 channel variants and offer insights into epilepsy's molecular underpinnings.