A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis

Strautnieks, Sandra; Bull, Laura N.; Knisely, A. S.; Kocoshis, S.; Dahl, Niklas; Arnell, Henrik; Sokal, Étienne; Dahan, Karin; Childs, Sarah J.; Ling,; Tanner, M S; Kagalwalla, Amir F.; Németh, Andrea H.; Pawłowska, Joanna; Baker, Alastair; Mieli‐Vergani, Giorgina; Freimer, Nelson B.; Gardiner, R. M.; Rj, Thompson

doi:10.1038/3034

Cited by 928 publications

(661 citation statements)

References 37 publications

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“…For example, although mutations in ATP8B1 and ABCB11 have been reported for subjects with severe forms of PFIC with low serum levels of gamma-glutamyltranspeptide (γGTP), specific mutations within each gene have also been associated with milder clinical phenotypes. 15,17,[24][25][26][27][28][29][30] Equally notable is the phenotypic pleomorphism of mutations in ABCB4, which ranges from high γGTP-PFIC (or PFIC3), to intrahepatic cholestasis of pregnancy, and gallstone formation, 19,25,[31][32][33][34][35][36] and an array of mutations in JAG1 in subjects with liver and/or non-hepatic malformations (e.g. : cardiovascular and renal defects).…”

Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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Background and Aims-Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the genes SERPINA1 (α1-antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1 (Progressive Familial Intrahepatic Cholestasis type 1/PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). However, the large gene sizes and lack of mutational hotspots make it difficult to survey for disease-causing mutations in clinical practice. Here, we aimed to develop a technological tool that reads out the nucleotide sequence of these genes rapidly and accurately.

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Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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“…Bile salt export pump (BSEP) deficiency is caused by mutations in ABCB11 1,2 . The severity of BSEP deficiency varies from progressive early-onset 1 to remitting and late-onset phenotypes [3][4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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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“…1 Later, PFIC1 (Byler disease) and PFIC2 were identified. [2][3][4] The term PFIC1 or FIC1 deficiency should be used preferentially.…”

Section: Greenland Familial Cholestasismentioning

confidence: 99%

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 1

Gonzalès¹,

Spraul

Jacquemin³

2013

Eur J Hum Genet

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A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis

Cited by 928 publications

References 37 publications

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

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

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 1

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