Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families
| Autor: | Anne Rayner, Etienne Sokal, A.S. Knisely, Peter F. Whitington, Hussa F. Al-Hussaini, Milan Jirsa, Bruno Stieger, Anthony Antoniou, Joanna Cielecka-Kuszyk, J A Byrne, Joanna Pawłowska, Henkjan J. Verkade, Ludmila Pawlikowska, Yvonne Meier, S S Strautnieks, Björn Fischler, Patricia McClean, Henrik Arnell, Benjamin L. Shneider, Richard J. Thompson, Figen Özçay, Sami Wali, Laura Dutton, Dita Cebecauerova, Radana Kotalova, Atif F. Bassas, Giorgina Mieli-Vergani, Laura N. Bull, Irena Jankowska, Antal Nemeth |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), University of Zurich, Strautnieks, S S |
| Rok vydání: | 2008 |
| Předmět: |
Male
Pathology LIVER CHILDREN Gene mutation medicine.disease_cause Polymerase Chain Reaction Gastroenterology Cholangiocarcinoma Risk Factors Genotype Missense mutation ABCB11 ATP Binding Cassette Transporter Subfamily B Member 11 Polymorphism Single-Stranded Conformational Mutation Incidence Liver Neoplasms Progressive familial intrahepatic cholestasis P-GLYCOPROTEIN DNA Neoplasm Immunohistochemistry INTRAHEPATIC CHOLESTASIS TYPE-2 Female HEREDITARY CHOLESTASIS BILIARY DIVERSION FARNESOID-X-RECEPTOR GENE-MUTATIONS EXPRESSION medicine.medical_specialty Carcinoma Hepatocellular Nonsense mutation 610 Medicine & health Cholestasis Intrahepatic Biology Cholestasis Internal medicine Confidence Intervals medicine Humans 2715 Gastroenterology Family Genetic Predisposition to Disease Alleles IDENTIFICATION Hepatology Sequence Analysis DNA medicine.disease United States Bile Ducts Intrahepatic Bile Duct Neoplasms 10199 Clinic for Clinical Pharmacology and Toxicology 2721 Hepatology ATP-Binding Cassette Transporters |
| Zdroj: | Gastroenterology, 134(4), 1203-1214. W B SAUNDERS CO-ELSEVIER INC |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2008.01.038 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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