Kidney360 · 2026
Type, Location and Zygosity of KCNJ16 Variants May Determine the Clinical Severity of Hypokalemia Tubulopathy and Deafness (HkTD).
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Gondra Leire, Mora Shivani, Shaikh Imran G, Garcia-Castaño Alejandro, Schilling Franziska, Ariceta Gema, García-Suarez Leire, Tejera-Carreño Patricia, Fernández-Juarez Gema, Rodríguez Alfredo Santana, Pujol-Giménez Jonai, García-Alonso Marta, Gómez-Conde Sara, Aranaga-Decori Ainhoa Camille, Koemhoff Martin, Renigunta Vijay, Weber Stefanie, Madariaga Leire, Renigunta Aparna
Аннотация
BACKGROUND: The pivotal role of Kir5.1 (KCNJ16) in maintaining electrolyte and acid-base homeostasis has been demonstrated in animal studies and highlighted by the identification of disease-causing variants in KCNJ16 resulting in Hypokalemia Tubulopathy and Deafness (HkTD) with variable severity. Although the underlying molecular mechanisms remain elusive, the modus operandi of Kir5.1 is deeply rooted in its heteromeric association with Kir4.1 (KCNJ10) and Kir4.2 (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 Kir5.1.
METHODS: In this study we performed whole exome sequencing for genetic screening. Functional studies were performed in Xenopus oocytes using two electrode voltage clamp recordings. Protein-protein interactions were determined by co-immunoprecipitation. Live cell imaging was performed using confocal microscopy to visualize the subcellular localization of the fluorescence tagged proteins using appropriate sub-cellular markers.
RESULTS: Here, we report 4 patients from 3 families with salt-losing tubulopathy, hypokalemia and acidosis secondary to pathogenic biallelic variants in KCNJ16. In addition to two previously described variants with phenotypic consistency (R137C) or phenotypic variability (I132R+R176*), we report a variant (K48*-Y57*) possibly lacking deafness, expanding the variant spectrum. Our results show that the pathogenic variants of Kir5.1 maintain interactions with Kir4.1 and Kir4.2 but differentially disrupt membrane trafficking of the heteromeric channels, offering a molecular explanation for the observed clinical heterogeneity.
CONCLUSIONS: HkTD is a clinically heterogenous disorder, where the onset, presentation and severity may be influenced by the type and location of the KCNJ16 variants. These variant specific effects on channel assembly, trafficking and residual function provide a mechanistic explanation for the broad spectrum of renal and auditory phenotypes and underscore the importance of molecular characterization for accurate diagnosis and personalized therapies.
METHODS: In this study we performed whole exome sequencing for genetic screening. Functional studies were performed in Xenopus oocytes using two electrode voltage clamp recordings. Protein-protein interactions were determined by co-immunoprecipitation. Live cell imaging was performed using confocal microscopy to visualize the subcellular localization of the fluorescence tagged proteins using appropriate sub-cellular markers.
RESULTS: Here, we report 4 patients from 3 families with salt-losing tubulopathy, hypokalemia and acidosis secondary to pathogenic biallelic variants in KCNJ16. In addition to two previously described variants with phenotypic consistency (R137C) or phenotypic variability (I132R+R176*), we report a variant (K48*-Y57*) possibly lacking deafness, expanding the variant spectrum. Our results show that the pathogenic variants of Kir5.1 maintain interactions with Kir4.1 and Kir4.2 but differentially disrupt membrane trafficking of the heteromeric channels, offering a molecular explanation for the observed clinical heterogeneity.
CONCLUSIONS: HkTD is a clinically heterogenous disorder, where the onset, presentation and severity may be influenced by the type and location of the KCNJ16 variants. These variant specific effects on channel assembly, trafficking and residual function provide a mechanistic explanation for the broad spectrum of renal and auditory phenotypes and underscore the importance of molecular characterization for accurate diagnosis and personalized therapies.