CLUSTERING OF PRIVATE MUTATIONS IN THE CONGENITAL CHLORIDE DIARRHEA DOWN-REGULATED IN ADENOMA GENE

An inherited defect in intestinal anion exchange, congenital chloride diarrhea (CLD), was recently shown to be caused by mutations in the do wn-regulated in adenoma (DRA) gene. A three base pair deletion resulti ng in the loss of an amino acid valine (V317del) in the predicted CLD/ DRA protein was shown to be responsible for all CLD cases in a Finnish founder population. Two additional mutations, H124L and 344delT, were found in Polish CLD patients. Here, we screened for additional mutati ons in a set of 14 CLD families of Polish, Swedish, North American, an d Finnish origin using primers that allowed mutation searches directly from genomic DNA samples, We found eight novel mutations in the CLD/D RA gene. The mutations included two transversions, one transition, one insertion, and four small deletions. Of II sequence alterations detec ted so far, nine he clustered in three short segments that are 49 hp, 39 bp, and 65 bp in size, respectively. These short segments span only 6.7% of the total cDNA length, suggesting functional importance or mu tation-prone DNA regions of the corresponding CLD/DRA protein domains. (C) 1998 Wiley-Liss, Inc.