IDENTIFICATION OF A MUTATION IN THE ILEAL SODIUM-DEPENDENT BILE-ACID TRANSPORTER GENE THAT ABOLISHES TRANSPORT ACTIVITY

The ileal Na+/bile acid cotransporter plays a critical role in the rea bsorption of bile acids from the small intestine. In the course of clo ning and characterizing the human ileal Na+/bile acid cotransporter cD NA, a dysfunctional isoform was identified in a patient diagnosed with Crohn's disease. Expression studies using hamster-human ileal Na+/bil e acid cotransporter cDNA chimeras narrowed the location of the defect to the carboxyl-terminal 94 amino acids. Comparison of the sequence o f the dysfunctional isoform to that of a wild-type human ileal Na+/bil e acid cotransporter genomic clone revealed a single C to T transition resulting in a proline to serine substitution at amino acid position 290. The inheritance of this mutation in the proband's family was conf irmed by single-stranded conformation polymorphism analysis and DNA se quencing. In transfected COS-l cells, the single amino acid change abo lished taurocholate transport activity but did not alter the transport er's synthesis or subcellular distribution. This dysfunctional mutatio n represents the first known molecular defect in a human sodium-depend ent bile acid transporter.