KCNJ16 – Hypokalemic Tubulopathy and Deafness

KCNJ16 encodes the inwardly rectifying potassium channel subunit Kir5.1, which forms heteromeric channels with Kir4.1 at the basolateral membrane of renal tubular cells. Biallelic pathogenic variants in KCNJ16 cause hypokalemic tubulopathy and deafness (HKTD), an autosomal recessive disorder characterized by renal salt wasting, metabolic acidosis, and sensorineural hearing loss.

To date, nine affected individuals from unrelated families have been reported with biallelic KCNJ16 variants, establishing a consistent autosomal recessive inheritance pattern ([PMID:37466410]). Segregation analysis in one kindred confirmed compound heterozygosity, and no other affected relatives beyond probands have been documented.

The variant spectrum comprises primarily missense changes altering channel function. In the index Chinese patient, two novel compound heterozygous variants, c.190A>C (p.Thr64Pro) and c.628C>G (p.His210Asp), were identified and shown to segregate with disease in the parents ([PMID:37466410]).

Functional studies demonstrate that HNF1β directly activates KCNJ16 transcription: HNF1β binding to the KCNJ16 promoter increases Kir5.1 expression 2.2-fold in luciferase assays, and Hnf1β knockout mice exhibit a 78% reduction in renal Kcnj16 transcripts ([PMID:28577853]).

CRISPR/Cas9‐derived KCNJ16–/– human kidney organoids recapitulate tubulopathy hallmarks including cyst formation, lipid droplet accumulation, and impaired TCA cycle flux; these phenotypes were ameliorated by simvastatin plus C75 treatment ([PMID:39183338]). Single-channel recordings in Kir5.1 knockout mouse proximal tubules confirm the loss of the 50-pS basolateral K+ conductance, supporting a loss-of-function mechanism ([PMID:39745541]).

A recent report of a homozygous I26T variant in an Amish patient and corresponding rat model showed no renal or channel abnormalities, indicating that variant position critically influences pathogenicity ([PMID:39414394]).

Collectively, multiple unrelated probands with biallelic KCNJ16 variants, consistent segregation, and convergent functional data support a strong gene–disease association. Early genetic diagnosis enables prompt electrolyte management and auditory screening.

Key Take-home: KCNJ16 biallelic variants cause autosomal recessive HKTD, and functional assays in organoids and animal models confirm loss-of-function, guiding diagnostic testing and potential statin-based therapies.

References

• Molecular genetics & genomic medicine • 2023 • Novel KCNJ16 variants identified in a Chinese patient with hypokalemic metabolic acidosis. PMID:37466410
• Kidney international • 2017 • Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease PMID:28577853
• Stem cell research & therapy • 2024 • KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment. PMID:39183338
• American journal of physiology. Renal physiology • 2025 • Kir5.1 regulates Kir4.2 expression and is a key component of the 50-pS inwardly rectifying potassium channel in basolateral membrane of mouse proximal tubules. PMID:39745541
• Physiological reports • 2024 • Characterization of a novel variant in KCNJ16, encoding Kir5.1 channel. PMID:39414394

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