SLC12A1 – Bartter syndrome type 1

Bartter syndrome type 1 is an autosomal recessive renal tubular disorder caused by biallelic loss-of-function variants in the solute carrier family 12 member 1 gene (SLC12A1), which encodes the furosemide-sensitive Na⁺-K⁺-2Cl⁻ cotransporter NKCC2. Clinically, affected neonates present antenatally with polyhydramnios, premature delivery, and postnatally with severe polyuria, salt wasting, hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, and failure to thrive (Bartter syndrome type 1).

To date, 72 unrelated BS type 1 patients harboring SLC12A1 mutations have been reported, involving 68 distinct pathogenic alleles detected in 129 of 144 studied alleles (PMID:28000888). The mutation spectrum includes missense, nonsense, splice-site, small insertions/deletions (1–4 nt), and recently recognized multi-exon deletions. All cases follow autosomal recessive inheritance with confirmed biallelic segregation in multiple unrelated families.

Variant classes identified encompass missense (e.g., c.1522G>A (p.Ala508Thr)), frameshifts (c.1833del (p.Phe611LeufsTer?)), and splice-site changes (c.1684+1G>A) demonstrating exon 13 skipping by minigene assay. A founder missense allele A555T has been noted in select populations. Novel compound heterozygous combinations continue to expand the allelic series underlying BS type 1.

Mechanistically, pathogenic SLC12A1 variants lead to NKCC2 dysfunction via haploinsufficiency and impaired trafficking. In vitro functional studies in Xenopus oocytes and mammalian cells confirm reduced or abolished cotransporter activity for missense and frameshift mutants (PMID:9585600). A Slc12a1I299F mouse replicates human polyuria, metabolic alkalosis, and electrolyte abnormalities, validating the loss-of-function model (PMID:20219826).

Phenotypic variability includes atypical early absence of hypokalemia or alkalosis and presentation mimicking nephrogenic diabetes insipidus, emphasizing the role of molecular testing in diagnosis even when classical biochemical signs are incomplete (PMID:10975303). No studies dispute the causative link between SLC12A1 variants and BS type 1.

Collectively, the evidence fulfills criteria for a definitive gene-disease relationship: numerous unrelated probands, consistent autosomal recessive inheritance, extensive variant spectrum, and concordant functional data. SLC12A1 genetic testing is clinically actionable, guiding timely antenatal counseling, neonatal management, and targeted therapeutic interventions.

References

• Molecular Medicine Reports • 2017 • Genetic heterogeneity in patients with Bartter syndrome type 1. PMID:28000888
• American Journal of Human Genetics • 1998 • Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. PMID:9585600
• American Journal of Physiology. Renal Physiology • 2010 • Mutation of the Na⁺-K⁺-2Cl⁻ cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia. PMID:20219826
• Nephrology (Carlton, Vic.) • 2024 • SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping. PMID:39258717
• Pediatric Nephrology • 2000 • Phenotypic variability in Bartter syndrome type I. PMID:10975303

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