Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Inwardly rectifying K+ channel 4.1 (Kir4.1), encoded by KCNJ10, is crucial for neuronal K+ homeostasis, primarily in astrocytes.
• Mutations in KCNJ10 are linked to Se સાથેAME/EAST syndrome, a disorder involving seizures, ataxia, deafness, and electrolyte imbalance.

Observation:

• Two siblings presented with seizures and motor delays, exhibiting compound heterozygous KCNJ10 missense mutations (p.A201T and p.I209T).
• Functional studies in CHO cells revealed that both mutations reduced K+ currents, impairing Kir4.1 channel activity.

Findings:

• The A201T mutation specifically decreased total and cell surface Kir4.1 levels, leading to channel instability and lysosomal degradation.
• While both mutations affected channel function, A201T additionally impacted Kir4.1 protein expression and stability.

Implications:

• These findings identify novel KCNJ10 mutations as causative agents for SeSAME/EAST-like syndrome.
• Understanding the distinct mechanisms of these mutations (functional impairment and protein instability) advances knowledge of Kir4.1 channelopathies.