SLC26A3 – Bartter syndrome

Variants in SLC26A3 do not cause classic Bartter syndrome (BS) but underlie congenital chloride diarrhea (CCD), which biochemically mimics BS. Patients presenting with hypokalemic hypochloremic metabolic alkalosis were initially diagnosed with BS but later reclassified as CCD upon identification of homozygous or compound heterozygous SLC26A3 frameshift mutations (e.g., c.1652delT (p.Phe551SerfsTer25)) and clinical correlation (PMID:31325522). Whole-exome sequencing uncovered SLC26A3 mutations in 5 individuals suspected of BS lacking mutations in known BS genes, confirming CCD and reversing the BS diagnosis (PMID:19861545). A targeted SLC26A3 screen in 10 patients with clinical BS/Gitelman features found no pathogenic variants, further refuting a causal role in BS (PMID:23756661). Functional assays in Xenopus oocytes demonstrate that SLC26A3 mutations abolish intestinal Cl⁻/HCO₃⁻ exchange, consistent with CCD pathogenesis and not with renal tubular defects of BS (PMID:9886994).

References

• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. PMID:19861545
• The Kobe journal of medical sciences • 2013 • SLC26A3 gene analysis in patients with Bartter and Gitelman syndromes and the clinical characteristics of patients with unidentified mutations. PMID:23756661
• The American journal of physiology • 1999 • Downregulated in adenoma gene encodes a chloride transporter defective in congenital chloride diarrhea. PMID:9886994

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