POSITIONAL CANDIDATE GENES FOR CONGENITAL CHLORIDE DIARRHEA SUGGESTEDBY HIGH-RESOLUTION PHYSICAL MAPPING IN CHROMOSOME REGION 7Q31

Congenital chloride diarrhea affects intestinal transportation of elec trolytes, resulting in potentially Fatal diarrhea. Linkage disequilibr ium analyses have suggested the congenital chloride diarrhea gene (CLD ) to lie within 0.37 cM from D7S496 in human chromosome 7q31. To clone the CLD gene, we have constructed and refined a physical map based on a 2.7-Mb YAC contig around D7S496 and identified two candidate genes. The physical positions of 4 known genes (DRA, PRKAR2B, LAMB1, DLD), 7 polymorphic repeat markers, and 13 CpG islands were established. DRA (down-regulated in adenoma) is expressed in the gut and encodes a prot ein with sequence homology to anion transporters, whereas PRKAR2B enco des a regulatory subunit for protein kinase A. Both genes map within 4 50 kb from D7S496, making them functionally and positionally relevant candidates for CLD.