Exon 1 was disrupted by a neomycin selection cassette inserted by homologous recombination. Protein was undetected by Western blot analysis of intestinal mucosal scrapings obtained from homozygous mutant mice. Total intestine mucosal guanylyl cyclase activity was reduced 16-fold relative to wild-type controls, whereas heat-stable enterotoxin (STa)-stimulable guanylyl cyclase activity was absent in mutant mice.