Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
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.
Strautnieks
Sandra S
SS
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, England. sandra.strautnieks@btinternet.com
Byrne
Jane A
JA
Pawlikowska
Ludmila
L
Cebecauerová
Dita
D
Rayner
Anne
A
Dutton
Laura
L
Meier
Yvonne
Y
Antoniou
Anthony
A
Stieger
Bruno
B
Arnell
Henrik
H
Ozçay
Figen
F
Al-Hussaini
Hussa F
HF
Bassas
Atif F
AF
Verkade
Henkjan J
HJ
Fischler
Björn
B
Németh
Antal
A
Kotalová
Radana
R
Shneider
Benjamin L
BL
Cielecka-Kuszyk
Joanna
J
McClean
Patricia
P
Whitington
Peter F
PF
Sokal
Etienne
E
Jirsa
Milan
M
Wali
Sami H
SH
Jankowska
Irena
I
Pawłowska
Joanna
J
Mieli-Vergani
Giorgina
G
Knisely
A S
AS
Bull
Laura N
LN
Thompson
Richard J
RJ
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
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004273:DNA, Neoplasm