SLC26A3 – Congenital Secretory Chloride Diarrhea

SLC26A3 (down-regulated in adenoma, DRA) is a solute carrier family 26 member that mediates electroneutral Cl⁻/HCO₃⁻ exchange in the ileum and colon. Pathogenic variants in SLC26A3 cause congenital secretory chloride diarrhea (CCD; MONDO:0008964), an autosomal recessive disorder characterized by life-long, Cl⁻-rich watery diarrhea, hypochloremic metabolic alkalosis, and electrolyte disturbances (PMID:39845277). Early prenatal signs include polyhydramnios and fetal intestinal dilation, facilitating antenatal suspicion and timely postnatal management.

Genetic evidence supports a definitive gene–disease relationship. Over 200 CCD probands from diverse populations have been reported, with more than 70 unique SLC26A3 variants including missense, nonsense, splice-site, small indels, and large deletions. Recurrent founder mutations such as c.2063-1G>T in East Asians and c.951_953del (p.Val318del) in Finns underscore population-specific allele frequencies. A representative loss-of-function allele is c.559G>T (p.Gly187Ter), which introduces a premature termination codon and segregates with disease in homozygous individuals (PMID:25568271).

Segregation analysis across multiple consanguineous and non-consanguineous families demonstrates homozygous or compound heterozygous inheritance of pathogenic SLC26A3 variants, consistent with autosomal recessive transmission. Carrier parents and siblings show heterozygosity without clinical phenotype, confirming full penetrance in biallelic cases.

Functional studies in Xenopus oocytes and mammalian cell systems reveal that CCD-causing mutations disrupt SLC26A3 transporter folding, trafficking, and anion exchange. Wild-type DRA catalyzes Cl⁻ and SO₄²⁻ transport and is stimulated by outward H⁺ gradients, whereas mutants such as p.Val318del lose Cl⁻/HCO₃⁻ exchange activity (PMID:9886994). STAS-domain mutations (e.g., p.Ile675dup, p.Gly393Trp) lead to misfolding and mistrafficking, abolishing cell surface expression and function (PMID:18216024).

The pathogenic mechanism involves loss of intestinal Cl⁻ absorption, resulting in osmotic diarrhea, volume contraction, and secondary hypokalemic, hypochloremic metabolic alkalosis. Lifelong oral NaCl and KCl supplementation effectively corrects electrolyte imbalance, enabling normal growth and avoiding renal and neurodevelopmental complications.

Key take-home: SLC26A3 genetic testing confirms CCD diagnosis, guides perinatal care, and enables targeted electrolyte therapy, markedly improving clinical outcomes.

References

• Radiology Case Reports • 2025 • Prenatally suspected and clinically diagnosed congenital chloride diarrhea. PMID:39845277
• Human Mutation • 2011 • Update on SLC26A3 mutations in congenital chloride diarrhea. PMID:21394828
• The American Journal of Physiology • 1999 • Downregulated in adenoma gene encodes a chloride transporter defective in congenital chloride diarrhea. PMID:9886994
• The Journal of Biological Chemistry • 2008 • Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. PMID:18216024
• Human Mutation • 1998 • A novel mutation of the down-regulated in adenoma gene in a Japanese case with congenital chloride diarrhea. PMID:10671059

Evidence Based Scoring (AI generated)