Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT

Carlton, Victoria; Harris, Baruch Z.; Puffenberger, Erik G.; Batta, Ashok K.; Knisely, A. S.; Robinson, Donna L.; Strauss, Kevin A.; Shneider, Benjamin L.; Lim, Wendell A.; Salen, Gerald; Morton, D. Holmes; Bull, Laura N.

doi:10.1038/ng1147

Cited by 292 publications

(187 citation statements)

References 22 publications

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“…33,34 Interestingly, patients with BAAT gene mutations also accumulated unconjugated bile acids in plasma. 35 Initial studies in which PEX2 mutants were fed conjugated bile acids, rather than unconjugated ones, have not shown any difference in growth or survival (P. Faust, unpublished data). Future investigations will further explore the efficacy of conjugated bile acid therapy.…”

Section: Discussionmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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The marked deficiency of peroxisomal organelle assembly in the PEX2 ؊/؊ mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2 ؊/؊ mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2 ؊/؊ mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation. Conclusion: Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease. (HEPATOLOGY 2007;45:982-997.)

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Section: Discussionmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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“…In these patients most of the unconjugated bile acids diffuse out of hepatocytes and into plasma, leading to high serum bile acid concentrations and low intestinal concentrations (29).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

165

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“…The severity of BSEP deficiency varies from progressive early-onset 1 to remitting and late-onset phenotypes [3][4][5][6][7] . Severe BSEP deficiency falls into the descriptive category of "progressive familial intrahepatic cholestasis" (PFIC) [8][9][10][11][12] , a heterogeneous group of autosomal recessive conditions that disrupt bile formation. BSEP deficiency is among disorders with low serum concentrations of γ-glutamyl transferase (γ-GT) activity despite conjugated hyperbilirubinaemia, as is familial intrahepatic cholestasis 1 (FIC1) deficiency caused by mutations in ATP8B1 13 .…”

Section: Introductionmentioning

confidence: 99%

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

et al. 2008

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BACKGROUND & AIMS:Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential. Abbreviations:ABC, ATP-binding cassette; AFP, α-fetoprotein; BSEP, bile salt export pump; CpG, cytosine-guanine; CC, cholangiocarcinoma; FIC1, familial intrahepatic cholestasis 1; γ-GT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; IC, intracellular loop; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NBF, nucleotide-binding fold; OLT, orthotopic liver transplantation; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PCR, polymerase chain reaction; RE, restriction endonuclease; SSCP, single-strand conformation polymorphism; TM, transmembrane domain; UDCA, ursodeoxycholic acid Acknowledgements We thank the families and the Children's Liver Disease Foundation for support and encouragement, and those who referred families for analysis, including Drs U Baumann, W Berquist, M de Vree, K Emerick, G Ferry, M Finegold, W Hardikar, S Horslen, R Houwen, R Jaffe, L Klomp, F Lacaille, K Mann, P McKiernan, H Sharp, R Sokol, E Sturm, L Szönyi, J Taminou, and J Watkins. We also thank Dr R Garcia-Kennedy for access...

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Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT

Cited by 292 publications

References 22 publications

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

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