Mutations of the Down–regulated in adenoma (DRA) gene cause congenital chloride diarrhoea

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Abstract
A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate1. We have studied a recessively inherited defect of this exchange, congenital chloride diarrhoea (CLD; MIM 214700)2. The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content. The CLD locus was previously mapped to 7q31 adjacent to the cystic fibrosis gene (CFTR)3. By refined genetic and physical mapping4,5, a cloned gene having anion transport function, Down-regulated in adenoma (DRA)6–8, was implicated as a positional and functional candidate for CLD. In this study, we report segregation of two missense mutations, ΔV317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients. The disease-causing nature of δV317 is supported by genetic data in relation to the population history of Finland9. By mRNA in situ hybridization, we demonstrate that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells, is unchanged in Finnish CLD patients with ΔV317, and is low in undifferentiated (including neoplastic) cells. We conclude that DFIA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated.