Kcnj16, encoding Kir5.1, is a gene of significant biological importance. Kir5.1, together with Kir4.1, constitutes a potassium channel located at the basolateral membranes of kidney tubular cells. This channel is crucial for controlling basolateral membrane potential and K+ recycling, which is coupled to Na-K-ATPase activity, thus playing a key role in renal Na+ handling and overall electrolyte and acid-base homeostasis [6,7].

In Kcnj16-depleted kidney organoids, there are transcriptomic and functional impairments of key voltage-dependent electrolyte and water-balance transporters, along with cysts formation, lipid droplet accumulation and fibrosis. Statins treatment can prevent lipid droplet accumulation and collagen-I deposition in these organoids, indicating potential therapeutic strategies for Kcnj16-related kidney defects [1]. Kcnj16 knockout in Dahl salt-sensitive rats leads to electrolyte/pH dysregulation, high-salt diet-induced mortality, increased light sensitivity, and reproducible sound-induced tonic-clonic audiogenic seizures. Dietary potassium supplementation can mitigate hypokalemia and prevent mortality from repeated seizures but not the seizures themselves [2]. In mice, Kcnj16 deletion doesn't seem to affect auditory function despite Kir5.1 being expressed in the cochlea [3]. Biallelic pathogenic variants in Kcnj16 result in hypokalemic tubulopathy and deafness (HKTD), a rare autosomal recessive disease. Novel compound heterozygous variants in Kcnj16 were detected in a Chinese patient with hypokalemic metabolic acidosis [4]. Kcnj16 gene ablation in mice causes subfertility and increases the prevalence of morphologically abnormal spermatozoa, suggesting its role in testis development, sperm flagellar morphology, motility, and fertility [5].

In summary, Kcnj16 plays essential roles in maintaining electrolyte and acid-base balance, especially in the kidney. Its functions also extend to the brain, potentially contributing to seizure disorders, and to male reproductive function. Gene knockout models in rats and mice have been invaluable in revealing these roles, providing insights into the pathophysiological mechanisms underlying related diseases and potential therapeutic directions for conditions such as kidney tubulopathy and certain neurological and reproductive disorders [1,2,3,4,5].

References:

1. Sendino Garví, E, van Slobbe, G J J, Zaal, E A, Janssen, M J, van Genderen, A M. 2024. KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment. In Stem cell research & therapy, 15, 268. doi:10.1186/s13287-024-03881-3. https://pubmed.ncbi.nlm.nih.gov/39183338/

2. Manis, Anna D, Palygin, Oleg, Isaeva, Elena, Hodges, Matthew R, Staruschenko, Alexander. 2021. Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat. In JCI insight, 6, . doi:10.1172/jci.insight.143251. https://pubmed.ncbi.nlm.nih.gov/33232300/

3. Lv, Jun, Fu, Xiaolong, Li, Yige, Huang, Yideng, Chai, Renjie. 2021. Deletion of Kcnj16 in Mice Does Not Alter Auditory Function. In Frontiers in cell and developmental biology, 9, 630361. doi:10.3389/fcell.2021.630361. https://pubmed.ncbi.nlm.nih.gov/33693002/

4. Chen, Jianxiong, Fu, Youqing, Sun, Yan, Li, Cong, Yuan, Haiming. 2023. Novel KCNJ16 variants identified in a Chinese patient with hypokalemic metabolic acidosis. In Molecular genetics & genomic medicine, 11, e2238. doi:10.1002/mgg3.2238. https://pubmed.ncbi.nlm.nih.gov/37466410/

5. Poli, Giulia, Hasan, Sonia, Belia, Silvia, Brancorsini, Stefano, D'Adamo, Maria Cristina. 2021. Kcnj16 (Kir5.1) Gene Ablation Causes Subfertility and Increases the Prevalence of Morphologically Abnormal Spermatozoa. In International journal of molecular sciences, 22, . doi:10.3390/ijms22115972. https://pubmed.ncbi.nlm.nih.gov/34205849/

6. Webb, Bryn D, Hotchkiss, Hilary, Prasun, Pankaj, Gelb, Bruce D, Satlin, Lisa. 2021. Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis. In European journal of human genetics : EJHG, 29, 1566-1569. doi:10.1038/s41431-021-00883-0. https://pubmed.ncbi.nlm.nih.gov/33840812/

7. Schlingmann, Karl P, Renigunta, Aparna, Hoorn, Ewout J, Zdebik, Anselm A, Konrad, Martin. 2021. Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness. In Journal of the American Society of Nephrology : JASN, 32, 1498-1512. doi:10.1681/ASN.2020111587. https://pubmed.ncbi.nlm.nih.gov/33811157/