KCNJ1 – Bartter syndrome type II

Bartter syndrome type II is an autosomal recessive renal tubulopathy caused by biallelic mutations in the ROMK channel gene, KCNJ1, leading to impaired potassium recycling and secondary Na–K–2Cl cotransporter dysfunction in the thick ascending limb of Henle’s loop. Clinically, patients present with polyuria, hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism, and nephrocalcinosis, often accompanied by hypercalciuria and growth delay. Although classically neonatal, late-onset and atypical presentations without overt alkalosis have been documented (PMID:32590952).

Genetic evidence includes at least 15 unrelated probands harboring pathogenic KCNJ1 variants: five single‐patient case reports of neonatal or late‐onset presentations and two multi‐patient cohorts comprising five Chinese probands (PMID:33058840) and five Italian patients followed longitudinally (PMID:20219833). Variants are inherited in trans (compound heterozygous) or homozygous states, and include missense, frameshift, and nonsense alleles across exons encoding pore, transmembrane, and cytosolic regions.

Segregation analysis in a multiplex kindred revealed three affected siblings with compound heterozygous S219R/L220F changes, confirming autosomal recessive inheritance with two additional affected relatives (PMID:24400161). The variant c.272C>T (p.Pro91Leu) exemplifies a recurrent missense change affecting channel conductance, reported in a premature infant with transient neonatal hyponatremia and persistent polyuria (PMID:32590952).

Functional assays have robustly demonstrated that KCNJ1 mutations reduce ROMK current amplitude and surface expression. Patch‐clamp recordings of variants V72E, D108H, P110L and others show <10% of wild-type currents (PMID:9015377), while ER‐associated degradation of misfolded alleles is implicated by stabilization upon proteasome inhibition in yeast and HEK293 models (PMID:28630040). Romk1 knockout mice exhibit impaired K⁺ excretion, underscoring in vivo relevance (PMID:26728465).

Phenotypic variability spans antenatal polyhydramnios and prematurity to adult‐onset hypokalemia with or without metabolic alkalosis. Nephrocalcinosis and hypercalciuria are consistent hallmarks, whereas acid–base disturbance may be absent in up to 40% of patients. Genotype–phenotype correlations remain incomplete but LoF alleles correlate with more severe antenatal presentations.

Collectively, extensive independent case reports, segregation in multiple families, and concordant functional data support a Definitive gene–disease association. Genetic testing for KCNJ1 variants is recommended in patients with unexplained hypokalemic alkalosis or isolated nephrocalcinosis, guiding diagnosis, management, and genetic counseling.

Key take-home: Biallelic KCNJ1 variants cause Bartter syndrome type II with variable onset; molecular confirmation enables precise diagnosis and informs renal electrolyte management.

References

• BMC Pediatr • 2020 • Transient hyponatremia of prematurity caused by mild Bartter syndrome type II: a case report. PMID:32590952
• Clin Chim Acta • 2020 • Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2. PMID:33058840
• Nephrol Dial Transplant • 2010 • Long-term follow-up of patients with Bartter syndrome type I and II. PMID:20219833
• Physiol Rep • 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
• Biochem Biophys Res Commun • 1997 • Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K+ channel function. PMID:9015377
• J Biol Chem • 2017 • Endoplasmic reticulum-associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome. PMID:28630040
• J Biol Chem • 2016 • Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion. PMID:26728465

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