Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss

Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2. Hearing loss: genetically tailored treatment strategy for congenital deafness People with a certain type of inherited hearing loss may stand to benefit from a personalized, genetically tailored treatment strategy. A research team from South Korea led by Byung Yoon Choi from Seoul National University College of Medicine identified three new mutations in KCNQ4, a gene that encodes a potassium channel protein found in the inner ear, that can cause congenital deafness. Strikingly, the authors identified the first hyperactive KCNQ4 variant. They inserted these gene variants into human cells in culture, and found that drugs known to affect the activity of this channel protein had different effects on different mutations. Impairments caused by two of the variants were prevented by drug treatment; the third variant proved resistant to the same therapeutic approach. The authors propose further validating the therapeutic responsiveness of different KCNQ4 variants in genetically engineered mice.

Automated summary

The study identified three novel KCNQ4 gene variants related to different auditory phenotypes, showing differential sensitivity to PIP2 and KCNQ openers. The findings suggest that gene mutations can be prevented from impairments through drug treatments, while some variants show resistance to therapeutic approaches.