title: Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, England. sandra.strautnieks@btinternet.com
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Strautnieks
authors.forename: Jane A
authors.initials: JA
authors.lastname: Byrne
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Dita
authors.initials: D
authors.lastname: Cebecauerová
authors.forename: Anne
authors.initials: A
authors.lastname: Rayner
authors.forename: Laura
authors.initials: L
authors.lastname: Dutton
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Meier
authors.forename: Anthony
authors.initials: A
authors.lastname: Antoniou
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Henrik
authors.initials: H
authors.lastname: Arnell
authors.forename: Figen
authors.initials: F
authors.lastname: Ozçay
authors.forename: Hussa F
authors.initials: HF
authors.lastname: Al-Hussaini
authors.forename: Atif F
authors.initials: AF
authors.lastname: Bassas
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.forename: Björn
authors.initials: B
authors.lastname: Fischler
authors.forename: Antal
authors.initials: A
authors.lastname: Németh
authors.forename: Radana
authors.initials: R
authors.lastname: Kotalová
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.forename: Joanna
authors.initials: J
authors.lastname: Cielecka-Kuszyk
authors.forename: Patricia
authors.initials: P
authors.lastname: McClean
authors.forename: Peter F
authors.initials: PF
authors.lastname: Whitington
authors.forename: Etienne
authors.initials: E
authors.lastname: Sokal
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
authors.forename: Sami H
authors.initials: SH
authors.lastname: Wali
authors.forename: Irena
authors.initials: I
authors.lastname: Jankowska
authors.forename: Joanna
authors.initials: J
authors.lastname: Pawłowska
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Thompson
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D001650:Bile Duct Neoplasms / Q000453:epidemiology / Q000209:etiology; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology; D018281:Cholangiocarcinoma / Q000453:epidemiology / Q000209:etiology; D002780:Cholestasis, Intrahepatic / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D016001:Confidence Intervals; D004273:DNA, Neoplasm / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014481:United States / Q000453:epidemiology
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004273:DNA, Neoplasm