Type, location and zygosity of KCNJ16 mutations may determine the clinical severity of Hypokalemic Tubulopathy and Deafness (HkTD)

Abstract The pivotal role of K ir 5.1 ( KCNJ16 ) in maintaining electrolyte and acid-base homeostasis was demonstrated by animal studies and highlighted by the identification of disease-causing mutations in KCNJ16 resulting in a complex tubulopathy with variable severity. Although the underlying molecular mechanisms remain elusive, the modus operandi of K ir 5.1 is rooted in its heteromeric association with K ir 4.1 ( KCNJ10 ) and K ir 4.2 ( KCNJ15 ). The ubiquitous expression of KCNJ16 and the heterogenous clinical picture point towards the importance of protein-protein interactions and membrane trafficking of the heteromeric channels involving K ir 5.1. Alongside a retrospective report on the R137C variant, we describe a divergent clinical phenotype in a patient compound heterozygous for I132R and R176*. Moreover, we characterize a novel variant (homozygous for K48* and Y57*) whose clinical presentation coincides with the phenotype of the Kcnj16 -/- mouse model (lack of deafness). Functional studies, buttressed by biomolecular studies (imaging and Co-IPs) in mammalian cells emphasize that the type and location of the KCNJ16 mutations may determine their interaction, membrane localization, and consequently, channel function and the resulting clinical phenotype. Our study highlights the need for molecular understanding of the KCNJ16 variants to promote correct diagnosis and personalized therapies, especially those involving channel modulators.