title: Identification of a mutation in the ileal sodium-dependent bile acid transporter gene that abolishes transport activity.
abstract: The ileal Na+/bile acid cotransporter plays a critical role in the reabsorption of bile acids from the small intestine. In the course of cloning and characterizing the human ileal Na+/bile acid cotransporter cDNA, a dysfunctional isoform was identified in a patient diagnosed with Crohn's disease. Expression studies using hamster-human ileal Na+/bile acid cotransporter cDNA chimeras narrowed the location of the defect to the carboxyl-terminal 94 amino acids. Comparison of the sequence of the dysfunctional isoform to that of a wild-type human ileal Na+/bile 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 confirmed by single-stranded conformation polymorphism analysis and DNA sequencing. In transfected COS-1 cells, the single amino acid change abolished taurocholate transport activity but did not alter the transporter's synthesis or subcellular distribution. This dysfunctional mutation represents the first known molecular defect in a human sodium-dependent bile acid transporter.
authors.affiliation: Department of Internal Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Wong
authors.forename: P
authors.initials: P
authors.lastname: Oelkers
authors.forename: P A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006031:Glycosylation; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D029363:Organic Anion Transporters, Sodium-Dependent; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D027981:Symporters; D013656:Taurocholic Acid / Q000378:metabolism; D014162:Transfection
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D029363:Organic Anion Transporters, Sodium-Dependent; D011993:Recombinant Fusion Proteins; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D012964:Sodium