Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl(-) /HCO 3- transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl(-) /HCO 3- exchange activity in vitro, and accordingly, evidence of genotype-phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance.
© 2011 Wiley-Liss, Inc.