Genetic Background of Congenital Chloride Diarrhea in High-Incidence Populations: Finland, Poland, and Saudi Arabia and Kuwait

Abstract

Congenital chloride diarrhea (CLD) is an inherited intestinal disorder caused by mutations in the down-regulated in adenoma gene. In Finland, the disease is prevalent because of a founder effect, and all but one of the CLD-associated chromosomes carry the same mutation, V317del. In Poland, another area with a high incidence of CLD, as many as seven different mutations have been detected so far. A third known cluster of CLD, around the Persian Gulf, has not been genetically studied. We studied the allelic diversity of CLD in Poland, in Saudi Arabia and Kuwait, and in three isolated families from North America and Hong Kong. Altogether, eight novel mutations were identified, making a total of 19 known CLD gene mutations. The Polish major mutation I675-676ins was found in 47% of the Polish CLD-associated chromosomes. Haplotype analysis and clustering of the I675-676ins mutation supported a founder effect and common ancestral origin. As in Finland, a major founder effect was observed in Arab patients: 94% of the CLD-associated chromosomes carried a nonsense mutation, G187X, which occurred in either a conserved ancestral haplotype or its derivative. Our data confirm that the same locus is mutated in all cases of CLD studied so far. In Poland, a relatively common founder mutation is likely to highlight a set of rare mutations that would very rarely produce homozygosity alone. This suggests that mutations in the CLD locus are not rare events. Although the disease is thought to be rare, undiagnosed patients may not be uncommon.

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

“…These data suggest that the ⌬Y526/7 mutation is extremely sensitive to its cellular environment and is possibly a less severe mutation than the I544N, I675/6ins or G702Tins mutations. It should be noted that the ⌬Y526/7 mutant was identified in a patient who had the severe I675/6ins mutation on the other SLC26A3 allele (69).…”

Mouse Down-regulated in Adenoma (DRA) Is an Intestinal Cl−/HCO3− Exchanger and Is Up-regulated in Colon of Mice Lacking the NHE3 Na+/H+Exchanger

“…It is unclear, however, whether sulfate transport is the major physiological function of DRA. Studies of humans with congenital chloride diarrhea (CLD), for which there is strong evidence of a defect in Cl Ϫ /HCO 3 Ϫ exchange in the ileum and colon (7)(8)(9), revealed that the disease was caused by null mutations in the DRA gene (10,11). This suggests that DRA might be a major transporter involved in Cl Ϫ absorption in the colon.…”

Surgical consequences in infants with delayed diagnosis of congenital chloride diarrhea

“…Chronic dehydration and renal impairment is a known complication of CCD (7,8). However, chronic dehydration can cause low fecal chloride concentration (reaching <40 mmol/L) (2) necessitating repeated fecal examinations.…”