Organic solute transporter- (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis

• Type of Material: Article
• Authors: Mutaz Sultan, Al-Qud University; Anuradha Rao, Emory University; Orly Elpeleg, Hebrew University Medical Center; Frederic M. Vaz, Academic Medical Center; Bassam Y Abu-Libdeh, Al-Qud University; Saul Karpen, Emory University; Paul A. Dawson, Emory University
• Language: English
• Date: 2018-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 by the American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.29516
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 68
• Issue: 2
• Start Page: 590
• End Page: 598
• Grant/Funding Information: This work was supported by NIH research grants DK056239 (S.J.K.) and DK047987 (P.A.D).
• Keywords: DISORDERS; METABOLISM; ALPHA-OST-BETA; BILE-ACID MALABSORPTION; LIVER; SUBUNIT; Science & Technology; EXPRESSION; Gastroenterology & Hepatology; Life Sciences & Biomedicine
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Primary bile acid malabsorption is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2) can cause primary bile acid malabsorption but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric organic solute transporter alpha-beta (OSTα-OSTβ; SLC51A-SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTβ deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma-glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. Conclusion: The findings identify OSTβ deficiency as a cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα-OSTβ's key role in the enterohepatic circulation of bile acids in humans.