Functional Screening of Kv7.5 Channel Variants Associated with Neuronal Dysfunction

Automated patch-clamp screening of heterozygous Kv7.5/Kv7.3 variants found gain-of-function for L341I+/-, G347S+/-, P369R+/-, and R497C+/- and loss-of-function for V145G+/- and W303C+/-.

• Why it matters: Kv7.5 variants linked to neurological dysfunction lack functional characterization, leaving causal links to pathogenicity unclear.
• What they did: The study performed the first automated patch clamp functional screen of nine heterozygous Kv7.5/Kv7.3 channel variants spanning diverse Kv7.5 locations, assessing voltage dependence and current density.
• The result: Gain-of-function variants left-shift activation and/or increase current density, while loss-of-function variants show reduced current density; z-score classification was initiated and XE991 sensitivity was higher in L341I+/-, G347S+/-, and P369R+/- variants.

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