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• W2327786045 abstract "Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene(SLC10A2). Oelkers P, Kirby LC, Heubi JE, Dawson PA.J Clin Invest 1997;99:1880-7. Summary: The molecular basis of congenital bile acid malabsorption in a previously reported case (Gastroenterology 1982; 83:804-11) is elegantly delineated in these studies from the Dawson laboratory. The genomic organization of the human SLC10A2 gene (also known as ASBT for apical sodium-dependent bile acid transporter) was characterized to permit single-stranded conformation polymorphism analysis (SSCP). SLC10A2, which was previously localized to human chromosome 13q33 (Genomics 1996; 33:538-40), consists of 6 exons spanning approximately 24 kb. Single-stranded conformation polymorphism analysis identified potentially relevant polymorphisms in exons 3, 4, and 5 of the affected patient. Sequence analysis revealed that these polymorphisms led to three missense mutations A171S, L243P, and T262M and a potential exon 3 splice-site junction mutation. The A171S and splice-site mutations were found on one allele, and the other two mutations were found on the second allele. To determine their relevance, site-specific mutations were introduced into constructs expressed in COS cells. The L243P and T262M mutations, when expressed individually or in tandem, resulted in a functionally defective bile acid transport protein. Results of cell surface labeling studies revealed that the mutated proteins were expressed on the surface of the COS cells, thereby excluding a membrane insertion problem as the cause of the loss of function. In contrast, A171S had no effect on bile acid transport activity. Presumably, although not experimentally proven, the splice-site junction mutation leads to the formation of an unstable SLC10A2 transcript or protein or a prematurely terminated and nonfunctional protein. Analysis of 104 control subjects did not reveal evidence of the splice-site mutation or either of the dysfunctional missense mutations. Comment: The modern era of the study of bile acid transport was ushered in by the expression cloning of the rat liver sodium-dependent bile acid transporter, ntcp (Proc Natl Acad Sci USA 1991; 88:10629-33). Subsequent application of this approach has resulted in cloning of the hamster ileal sodium-dependent bile acid transporter (J Biol Chem 1994; 269:1340-7). Homologues of these two genes have been identified in other species so that molecular probes for rat, hamster, and human transporters are readily available. These discoveries have led to a wide array of advances in our understanding of bile acid transport and its regulation. Clearly one of the primary goals of these and future investigations is to elucidate the role of defects in bile acid transporters in human disease. The studies of Oelkers et al. are the first molecular description of a bile acid transporter defect in a patient with clinical and biochemical evidence of a bile acid transport defect. Prediction of the clinical phenotype of an apical ileal bile acid transport abnormality is relatively straightforward-if it is presumed that there are not quantitatively important redundant systems for intestinal reclamation of bile salts-and it was predicted in early investigations of the enterohepatic circulation of bile salts and bile salt diarrhea (Arch Int Med 1972; 130: 552-73, 597-605; Gut 1976; 17:965-70). Primary malabsorption of bile salts would be expected to result in significant diarrhea on the basis of osmotic load, detergent, and receptor-mediated secretory effects of bile salts in the colon, and fat malabsorption secondary to overall depletion of the bile salt pool. Findings in ileal histologic and radiographic studies would be expected to be normal. Bile acid malabsorption should be evident by appropriate clinical testing, including the measurement of fecal bile acids and testing of intestinal bile acid reclamation (postprandial bile salt elevation[J Pediatr 1979; 96:582-9 or [75Se]-HCAT retention[Gastroenterology 84:63-8]). In vitro analysis of bile salt transport, when feasible, should produce be abnormal results. Although these clinical investigations (J Pediatr 1979; 94:546-51; J Pediatr 1980; 96:582-9;Gastroenterology 1982; 83:804-11) have carefully been documented in several cases, the existence of a primary genetic defect in ileal apical bile acid transport remains controversial (Scand J Gastroenterol 1992; 27[suppl]194:66-70). The patient who was studied by Oelkers et al. met all of the described criteria for a primary abnormality in apical ileal bile acid transport and had two distinctively different abnormalities in hisSLC10A2 alleles. One allele had two separate dysfunctional missense mutations, whereas the second had a donor splice-site abnormality, which presumably would yield a truncated and dysfunctional transport protein. Ultimately, it would be interesting to see this second point addressed, either by immunohistochemical analysis of ileal biopsy specimens from the patient or by expression of a minigene construct in vitro. It is of interest that this is not the first example of a mutation leading to an ileal bile acid transport defect. In the process of cloning the human SLC10A2 complementary DNA, a dysfunctional missense mutation (P290S) in ASBT was identified in a patient who was heterozygous for the defect and was revelingly clinically asymptomatic (J Biol Chem 270:27228-34). It is notable that this is the second sodium-solute cotransporter gene associated with intestinal malabsorption, the first being the sodium-glucose transporter (SGLT1) associated with glucose-galactose malabsorption (Nature 350:354-6). These findings have important implications for our understanding of ileal bile acid transport and of cholesterol metabolism (J Clin Invest 1997; 99:1807-8). In addition, these studies are the opening of a new area of investigations and understanding of human disease, especially as it pertains to bile acid transport. The complexities of bile acid transport are manifest by the number of transport processes that have been described (Pediatr Res 1997; 42:2, cover). Current findings indicate that the ASBT gene product is expressed on the apical surface of ileal enterocytes, renal proximal convoluted tubules, and cholangiocytes (J Clin Invest 1995; 95:745-54; Am J Physiol 1996; 271:G377-85;Gastroenterology 1997; 113:1734-40; J Clin Invest, in press). The apparent absence of biliary, hepatic, and renal disease in the patient characterized by Oelkers et al., suggests that ASBT function is not essential in these organs and that dysfunction does not cause injury or disease. Elucidation of the functional role of biliary and renal ASBT will therefore be unlikely to become readily apparent from knockout studies and will require relatively sophisticated physiologic studies, potentially in the context of tissue-specific ablation of function. Molecular descriptions of abnormalities in hepatic transport of bile acids have not yet been described. Cloning of the hepatic sinusoidal sodium-dependent bile acid transporter, ntcp (SLC10A1), nearly 3 years before ASBT has not led to the identification of a similar transporter defect (Proc Natl Acad Sci USA 1991; 88:10629-33). It had been previously suggested that such a defect might result in a clinical phenotype consisting of relatively isolated hypercholanemia (J Pediatr Gastroenterol Nutr 1995; 20:233-5). Molecular investigation of two patients with clincial phenotype has not revealed a primary defect in theNTCP gene (Hepatology 1997; 25:1176-83). Four more patients from the Amish community have recently been described who also appear to have an abnormality in hepatic extraction of bile acids(Gastroenterology 1997; 112:A1338). Molecular analyses of these patients have not yet been performed. Abnormalities in canalicular transport of bile acids are probably involved in several inherited cholestatic liver diseases. These clinically important disorders are referred to descriptively as progressive familial intrahepatic cholestasis, with Byler's disease as the prototype (Am J Dis Child 1969; 117:112-4; J Pediatr Gastroenterol Nutr 1994; 18:128-33, 134-41; Hepatology 1997; 26:155-64) Remarkably low biliary bile acid concentrations have been measured in children with a clinical phenotype consistent with a specific defect in canalicular excretion of bile salts(Eur J Pediatr 1994; 153:424-8). Preliminarily, a defect in the canalicular phospholipid flippase, MDR 3, has been described in a child with familial intrahepatic cholestasis and high γ-glutamyl transpeptidase levels (Hepatology 1996; 23:904-8). The uncharacterized molecular nature of the adenosine triphosphate-dependent canalicular bile acid transporter has impeded advances in this important area of investigation, although it seems likely that significant progress in its identification is imminent. Investigators are applying several cloning strategies to this problem, including molecular biologic and genetic approaches (Proc Natl Acad Sci USA 1995; 92:5421-5; Hum Mol Genet 1995; 4:1049-53;Hepatology 1997; 26:155-64; J Med Genet 1996; 33:833-6;Hepatology 1997; 26:383A). It will be of interest to see whether these distinct approaches yield similar answers and whether the answers give further insight into the mechanism involved in hereditary cholestasis. Benjamin L. Shneider Divison of Pediatric Gastroenterology; Mt. Sinai Medical Center; New York, New York, U.S.A." @default.
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• W2327786045 title "A New Era in Bile Acid Transport Pathophysiology" @default.
• W2327786045 doi "https://doi.org/10.1097/00005176-199802000-00025" @default.
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