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

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 mapping^4,5, 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, V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients. The disease-causing nature of V317 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 V317, and is low in undifferentiated (including neoplastic) cells. We conclude that DFIA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated.

1. Buchan, A.M.J. Digestion and absorption. in Textbook of Physiology, (eds Patton, H.D., Fuchs, A.F., Hille, B., Scher A.M. & Steiner, R. ) 1438−1460 (Saunders Company, London, 1989).
2. Norio, R., Perheentupa, J., Launiala, K. & Hallman, N. Congenital chloride diarrhea, an autosomal recessive disease. Clin. Genet. 2, 182−192 (1971). | PubMed  | ChemPort |
3. Kere, J., Sistonen, P., Holmberg, C. & de la Chapelle, A. The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator. Proc. Natl. Acad. Sci. USA 90, 10686−10689 (1993). | PubMed  | ChemPort |
4. Höglund, P. et al. Fine mapping of the congenital chloride diarrhea gene by linkage disequilibrium. Am. J. Hum. Genet. 57, 95−102 (1995). | PubMed  | ISI |
5. Höglund, P. et at. Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31. Genome Res. 6, 202−210 (1996). | PubMed  | ISI |
6. Schweinfest, C.W., Henderson, K.W., Suster, S., Kondoh, N. & Papas, T.S. Identification of a colon mucosa gene that is down-regulated in colon adenomas and adenocarcinomas. Proc. Natl. Acad. Sci. USA 90, 4166−4170 (1993). | PubMed  | ChemPort |
7. Silberg, D.G., Wang, W., Moseley, R.H. & Traber, P.G., The Down regulated in adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein. J. Biol. Chem. 270, 11897−11902 (1995). | Article | PubMed  | ISI | ChemPort |
8. Byeon, M.K. et al. The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein. Oncogene 12, 387−396 (1996). | PubMed  | ISI | ChemPort |
9. de la Chapelle, A. Disease gene mapping in isolated human populations: the example of Finland. J. Med. Genet. 30, 857−865 (1993). | PubMed  | ChemPort |
10. Turnberg, L.A. Abnormalities in intestinal electrolyte transport in congenital chloridorrhoea. Gut 12, 544−551 (1971). | PubMed  | ISI | ChemPort |
11. Bieberdorf, F.A., Gorden, P. & Fordtran, J.S. Patnogenesis of congenital alkalosis with diarrhea. J. Clin. Invest. 51, 1958−1968 (1972). | PubMed  | ISI | ChemPort |
12. Pearson, A.J.G. et al. The pathophysiology of congenital chloridorrhoea. Q. J. Med. 167, 453−466 (1973).
13. Holmberg, C., Perheentupa, J. & Launiala, K. Colonic electrolyte transport in health and in congenital chloride diarrhea. J. Clin. Invest. 56, 302−310 (1975). | PubMed  | ISI | ChemPort |
14. Tomaszewski, L., Kulesza, E. & Socha, J. Congenital chloride diarrhoea in Poland. Mat Med. Pol. 4, 271−277 (1987).
15. Hästbacka, J. et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073−1087 (1994). | Article | PubMed  | ISI | ChemPort |
16. Trezise, A.E.O. & Buchwald, M. In vivo Cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature 353, 434−437 (1991). | Article | PubMed  | ISI | ChemPort |
17. Strong, T.V., Boehm, K. & Collins, F.S. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization. J. Clin. Invest. 93, 347−354 (1994). | PubMed  | ISI | ChemPort |
18. Hästbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204−211 (1992). | PubMed  | ISI | ChemPort |
19. Lehesjoki, A.-E. et al. Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping. Hum. Mol. Genet. 2, 1229−1234 (1993). | PubMed  | ISI | ChemPort |
20. Saarialho-Kere, U.K. et al. Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J. Clin. Invest. 92, 2858−2866 (1993). | PubMed  | ChemPort |
21. Prosser, I.W. et al. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridisation. Am. J. Pathol. 135, 1073−1088 (1989). | PubMed  | ISI | ChemPort |
22. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152−154 (1996). | Article | PubMed  | ISI | ChemPort |

	Top

	Top