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Research Article Free access | 10.1172/JCI119355

Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2).

P Oelkers, L C Kirby, J E Heubi, and P A Dawson

Department of Internal Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA.

Find articles by Oelkers, P. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA.

Find articles by Kirby, L. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA.

Find articles by Heubi, J. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA.

Find articles by Dawson, P. in: JCI | PubMed | Google Scholar

Published April 15, 1997 - More info

Published in Volume 99, Issue 8 on April 15, 1997
J Clin Invest. 1997;99(8):1880–1887. https://doi.org/10.1172/JCI119355.
© 1997 The American Society for Clinical Investigation
Published April 15, 1997 - Version history
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Abstract

Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels. The molecular basis of PBAM is unknown, and several conflicting mechanisms have been postulated. In this study, we cloned the human ileal Na+/bile acid cotransporter gene (SLC10A2) and employed single-stranded conformation polymorphism analysis to screen for PBAM-associated mutations. Four polymorphisms were identified and sequenced in a family with congenital PBAM. One allele encoded an A171S missense mutation and a mutated donor splice site for exon 3. The other allele encoded two missense mutations at conserved amino acid positions, L243P and T262M. In transfected COS cells, the L243P, T262M, and double mutant (L243P/T262M) did not affect transporter protein expression or trafficking to the plasma membrane; however, transport of taurocholate and other bile acids was abolished. In contrast, the A171S mutation had no effect on taurocholate uptake. The dysfunctional mutations were not detected in 104 unaffected control subjects, whereas the A171S was present in 28% of that population. These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile acids.

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