KCNJ1 – Bartter Syndrome Type II

KCNJ1 encodes the renal outer medullary potassium channel ROMK, which recycles K⁺ across the apical membrane of thick ascending limb cells to support Na⁺–K⁺–2Cl⁻ cotransport. Autosomal recessive loss-of-function variants in KCNJ1 cause Bartter syndrome type II, an antenatal/neonatal salt-wasting tubulopathy characterized by polyhydramnios, premature birth, polyuria, hypokalemic metabolic alkalosis, hypercalciuria, and nephrocalcinosis (PMID:24400161).

1 Clinical Validity

Over 19 unrelated probands with KCNJ1 variants have been reported (PMID:37763757), with segregation analyses in three multiplex families demonstrating co-segregation of compound heterozygous or homozygous alleles (PMID:24400161; PMID:34751387). Functional concordance is established by multiple in vitro studies showing loss of ROMK channel activity. The body of evidence meets the ClinGen criteria for a Definitive gene–disease relationship.

2 Genetic Evidence

Inheritance is autosomal recessive. Segregation in a family with three affected siblings and in a pedigree with six additional affected relatives confirms familial linkage (PMID:24400161; PMID:34751387). Over 19 probands harbor diverse variant classes, including missense and nonsense changes, frameshifts, and splice variants. A representative pathogenic allele is c.701C>T (p.Thr234Ile) found in adult-onset BS2 (PMID:31441846). No recurrent founder variants have been described for KCNJ1.

3 Functional Evidence

Electrophysiologic assays in Xenopus oocytes and mammalian cells demonstrate that multiple BS2-associated KCNJ1 mutations (e.g., p.Ser200Arg, p.Leu201Phe, p.Val296Gly) severely impair ROMK-mediated K⁺ currents, via defective gating, trafficking, or stability (PMID:9015377; PMID:24400161). ER-associated degradation studies reveal misfolded channels degraded by the proteasome, confirming a loss-of-function mechanism (PMID:28630040).

4 Integration and Conclusion

The cumulative genetic and experimental data—19 probands with pathogenic KCNJ1 variants, familial segregation, and robust functional impairment—support a Definitive clinical validity classification. Genetic testing of KCNJ1 is essential for early diagnosis of BS2, guiding perinatal management of polyhydramnios and neonatal electrolyte correction. Identification of causative alleles enables accurate prognostication, targeted therapy, and informed reproductive counseling.

Key Take-home: Loss-of-function KCNJ1 variants cause autosomal recessive Bartter syndrome type II, and comprehensive genetic and functional evidence supports routine KCNJ1 testing in suspected neonatal salt-wasting tubulopathies for definitive diagnosis and management.

References

• Physiological reports • 2013 • Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity. PMID:24400161
• Medicina • 2023 • Bartter Syndrome: A Systematic Review of Case Reports and Case Series. PMID:37763757
• Medicine • 2019 • A novel compound heterozygous KCNJ1 gene mutation presenting as late-onset Bartter syndrome: Case report. PMID:31441846
• Biochemical and biophysical research communications • 1997 • Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K+ channel function. PMID:9015377
• The Journal of biological chemistry • 2017 • Endoplasmic reticulum-associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome. PMID:28630040

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