SLC12A1 – Bartter syndrome

SLC12A1 encodes the bumetanide-sensitive Na⁺-K⁺-2Cl⁻ cotransporter NKCC2 expressed in the thick ascending limb of Henle’s loop. Biallelic loss-of-function variants in SLC12A1 cause autosomal recessive Bartter syndrome type I, characterized by salt wasting, hypokalemic alkalosis, and hypercalciuria. These features often present antenatally with polyhydramnios and premature delivery.

Genetic Evidence

Bartter syndrome type I displays an autosomal recessive inheritance pattern with numerous unrelated probands harboring SLC12A1 variants. In a cohort of 15 families, frameshift and nonconservative missense mutations (e.g. c.1670del (p.Ala557fs)) co-segregated with disease in all affected individuals ([PMID:8640224]). A founder variant, c.1875G>A (p.Trp625Ter), was identified in 20 Costa Rican antenatal Bartter patients on a common haplotype, confirming a population-specific allele ([PMID:9355073]). Compound heterozygotes and homozygotes have been reported across diverse ethnicities, with over 30 distinct alleles described.

Variant Spectrum & Segregation

The SLC12A1 mutational spectrum includes frameshift (e.g. c.1166dup (p.Ala390fs)), nonsense (e.g. c.2584A>T (p.Lys862Ter)), splice-site (c.725-1G>A), and missense changes (e.g. c.905G>A (p.Arg302Gln)). Segregation in consanguineous families and multiplex sibships accounts for ≥17 additional affected relatives, supporting recessive inheritance.

Functional Evidence

In vitro expression of mutant NKCC2 in Xenopus oocytes demonstrates severely reduced bumetanide-sensitive Rb⁺ uptake for frameshift and missense alleles, with residual activity correlating with milder phenotypes. Knock-in and knockout mouse models recapitulate polyuria, hypotension, metabolic alkalosis, and nephrocalcinosis seen in patients. Cellular studies reveal ER retention of COOH-terminal truncations and impaired glycosylation, consistent with deficient surface trafficking.

Clinical Correlation & Mechanism

Patients present antenatally with polyhydramnios, premature birth, and early onset polyuria. Biochemical hallmarks include hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypercalciuria. Pathogenic variants result in loss of NKCC2 function, leading to salt wasting and compensatory secondary hyperaldosteronism. Early genetic diagnosis guides management with electrolyte supplementation and NSAIDs.

Key Take-home: Definitive evidence links biallelic SLC12A1 variants to autosomal recessive Bartter syndrome type I; genetic testing and functional assays enable precise diagnosis and tailored treatment.

References

• Nature genetics • 1996 • Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. PMID:8640224
• Journal of the American Society of Nephrology • 1997 • A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect. PMID:9355073

Evidence Based Scoring (AI generated)