The University of Southampton
University of Southampton Institutional Repository

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families
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
p-glycoprotein, hereditary cholestasis, gene-mutations, expression, biliary diversion, farnesoid-x-receptor, identification, liver, intrahepatic cholestasis type-2, children
0016-5085
1203-1214
Strautnieks, Sandra S.
709d1467-c2a5-4ded-966f-df24953adea5
Byrne, Jane A.
ce947258-ed9a-40e6-8dae-f538965b50a1
Pawlikowska, Ludmila
e3abe412-8c49-440f-b8c9-eb6d2cdf6eed
Cebecauerova, Dita
83ffdbda-30a7-46f1-a1a5-369c96423e38
Rayner, Anne
24696183-13ea-416d-aeee-69691f0d9a13
Dutton, Laura
ad0201d8-7530-47ae-8961-bd2edf9ef2dc
Meier, Yvonne
da175547-9966-4d66-b864-fdc6281e1b8c
Antoniou, Anthony
538efe60-8406-4414-ba43-9946d50f74c8
Stieger, Bruno
45a2ce5b-a6ec-4b74-8b66-1ca48fd1e890
Arnell, Henrik
485c3d6a-4fa8-41cd-bd70-29c93b714228
Ozcay, Figen
283b6a9c-a658-4461-a002-df0ef2c1560d
Al-Hussaini, Hussa F.
5d8fc9f3-afca-42bf-9c8f-9a4e88ee7562
Bassas, Atif F.
2ce4e581-1cde-4389-89dc-51185c19effc
Verkade, Henkjan J.
7e13a900-45fe-4f91-8d85-f157f0d9f39a
Fischler, Bjorn
390801e9-7e8f-4ed4-b52d-689a0f3cdff5
Nemeth, Antal
52d6d66f-f56f-4465-8b56-70f3ae6aecc1
Kotalova, Radana
c99c82e3-1f3e-4a99-a0a8-7287a39eb46e
Shneider, Benjamin L.
406dd0ea-6f64-4307-be0c-5862d4fffc06
Cielecka-Kuszyk, Joanna
50ffca5e-de18-4a40-8f41-4904418531e1
McClean, Patricia
fd95f6bf-a0c9-42ef-9e3e-881b3b4c04e0
Whitington, Peter F.
8803f801-ede3-4f4c-b938-185ee9f1ab64
Sokal, Etienne
7c4a2137-4796-4157-a94d-222deaf45cea
Jirsa, Milan
dafc5374-a324-486e-87c1-ea1daf3d5914
Wali, Sami H.
f65d3869-0787-4552-9f8d-792883986a24
Jankowska, Irena
7e53807c-a503-45db-b063-e0b35e8e01c3
Pawlowska, Joanna
098a7505-63a6-4f15-8979-0923bdc18f17
Mieli-Vergani, Giorgina
922c17cb-565d-437c-91aa-8c4e334d3d97
Knisely, A.S.
6efbb1c6-9875-4498-a2c4-640e48c9e2f7
Bull, Laura N.
406e6bf9-a04e-4a79-bdab-b494bdf25d79
Thompson, Richard J.
ef6e1d24-41c1-487c-ac54-824e3e5f1c5a
Strautnieks, Sandra S.
709d1467-c2a5-4ded-966f-df24953adea5
Byrne, Jane A.
ce947258-ed9a-40e6-8dae-f538965b50a1
Pawlikowska, Ludmila
e3abe412-8c49-440f-b8c9-eb6d2cdf6eed
Cebecauerova, Dita
83ffdbda-30a7-46f1-a1a5-369c96423e38
Rayner, Anne
24696183-13ea-416d-aeee-69691f0d9a13
Dutton, Laura
ad0201d8-7530-47ae-8961-bd2edf9ef2dc
Meier, Yvonne
da175547-9966-4d66-b864-fdc6281e1b8c
Antoniou, Anthony
538efe60-8406-4414-ba43-9946d50f74c8
Stieger, Bruno
45a2ce5b-a6ec-4b74-8b66-1ca48fd1e890
Arnell, Henrik
485c3d6a-4fa8-41cd-bd70-29c93b714228
Ozcay, Figen
283b6a9c-a658-4461-a002-df0ef2c1560d
Al-Hussaini, Hussa F.
5d8fc9f3-afca-42bf-9c8f-9a4e88ee7562
Bassas, Atif F.
2ce4e581-1cde-4389-89dc-51185c19effc
Verkade, Henkjan J.
7e13a900-45fe-4f91-8d85-f157f0d9f39a
Fischler, Bjorn
390801e9-7e8f-4ed4-b52d-689a0f3cdff5
Nemeth, Antal
52d6d66f-f56f-4465-8b56-70f3ae6aecc1
Kotalova, Radana
c99c82e3-1f3e-4a99-a0a8-7287a39eb46e
Shneider, Benjamin L.
406dd0ea-6f64-4307-be0c-5862d4fffc06
Cielecka-Kuszyk, Joanna
50ffca5e-de18-4a40-8f41-4904418531e1
McClean, Patricia
fd95f6bf-a0c9-42ef-9e3e-881b3b4c04e0
Whitington, Peter F.
8803f801-ede3-4f4c-b938-185ee9f1ab64
Sokal, Etienne
7c4a2137-4796-4157-a94d-222deaf45cea
Jirsa, Milan
dafc5374-a324-486e-87c1-ea1daf3d5914
Wali, Sami H.
f65d3869-0787-4552-9f8d-792883986a24
Jankowska, Irena
7e53807c-a503-45db-b063-e0b35e8e01c3
Pawlowska, Joanna
098a7505-63a6-4f15-8979-0923bdc18f17
Mieli-Vergani, Giorgina
922c17cb-565d-437c-91aa-8c4e334d3d97
Knisely, A.S.
6efbb1c6-9875-4498-a2c4-640e48c9e2f7
Bull, Laura N.
406e6bf9-a04e-4a79-bdab-b494bdf25d79
Thompson, Richard J.
ef6e1d24-41c1-487c-ac54-824e3e5f1c5a

Strautnieks, Sandra S., Byrne, Jane A., Pawlikowska, Ludmila, Cebecauerova, Dita, Rayner, Anne, Dutton, Laura, Meier, Yvonne, Antoniou, Anthony, Stieger, Bruno, Arnell, Henrik, Ozcay, Figen, Al-Hussaini, Hussa F., Bassas, Atif F., Verkade, Henkjan J., Fischler, Bjorn, Nemeth, Antal, Kotalova, Radana, Shneider, Benjamin L., Cielecka-Kuszyk, Joanna, McClean, Patricia, Whitington, Peter F., Sokal, Etienne, Jirsa, Milan, Wali, Sami H., Jankowska, Irena, Pawlowska, Joanna, Mieli-Vergani, Giorgina, Knisely, A.S., Bull, Laura N. and Thompson, Richard J. (2008) Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology, 134 (4), 1203-1214. (doi:10.1053/j.gastro.2008.01.038).

Record type: Article

Abstract

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

This record has no associated files available for download.

More information

Published date: April 2008
Keywords: p-glycoprotein, hereditary cholestasis, gene-mutations, expression, biliary diversion, farnesoid-x-receptor, identification, liver, intrahepatic cholestasis type-2, children

Identifiers

Local EPrints ID: 62935
URI: http://eprints.soton.ac.uk/id/eprint/62935
ISSN: 0016-5085
PURE UUID: 34c8e51d-1a89-4890-b353-2faa8ed1aaa4

Catalogue record

Date deposited: 02 Sep 2008
Last modified: 15 Mar 2024 11:33

Export record

Altmetrics

Contributors

Author: Sandra S. Strautnieks
Author: Jane A. Byrne
Author: Ludmila Pawlikowska
Author: Dita Cebecauerova
Author: Anne Rayner
Author: Laura Dutton
Author: Yvonne Meier
Author: Anthony Antoniou
Author: Bruno Stieger
Author: Henrik Arnell
Author: Figen Ozcay
Author: Hussa F. Al-Hussaini
Author: Atif F. Bassas
Author: Henkjan J. Verkade
Author: Bjorn Fischler
Author: Antal Nemeth
Author: Radana Kotalova
Author: Benjamin L. Shneider
Author: Joanna Cielecka-Kuszyk
Author: Patricia McClean
Author: Peter F. Whitington
Author: Etienne Sokal
Author: Milan Jirsa
Author: Sami H. Wali
Author: Irena Jankowska
Author: Joanna Pawlowska
Author: Giorgina Mieli-Vergani
Author: A.S. Knisely
Author: Laura N. Bull
Author: Richard J. Thompson

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×