The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Deafness-associated genes KCNQ1 (also associated with heart diseases) and KCNQ4 (only associated with hearing loss) encode the homotetrameric voltage-gated potassium ion channels Kv7.1 and Kv7.4, respectively. To date, over 700 KCNQ1 and over 70 KCNQ4 variants have been identified in patients. The vast majority of these variants are inherited dominantly, and their pathogenicity is often explained by dominant-negative inhibition or haploinsufficiency. Our recent study unexpectedly identified cell-death-inducing cytotoxicity in several Kv7.1 and Kv7.4 variants. Elucidation of this cytotoxicity mechanism and identification of its modifiers (drugs) have great potential for aiding the development of a novel pharmacological strategy against many pathogenic KCNQ variants. The purpose of this review is to disseminate this emerging pathological role of Kv7 variants and to underscore the importance of experimentally characterizing disease-associated variants.