ABCMdb

PMID: 16871584

Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F, Laszlo A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Nemeth A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawlowska J, Melin-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ
Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
Hepatology. 2006 Aug;44(2):478-86., [PubMed]

Sentences

No. Mutations Sentence Comment

66 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Tyr472* ABCB11 p.Tyr472* ABCB11 p.Tyr772* Patients, Clinical Courses, and ABCB11 / BSEP Mutations Patient/Gender; Origins Sibling(s) With PFIC Age, PFIC Manifest Intervention(s) Age, HCC Diagnosed Outcome to Date Nucleotide Changes Predicted Consequences A/Male; Northern European Caucasian 0 Cholestasis from 3 wk Hepatocyte infusion, 16 mo 21 mo (incidental in explant; AFP 199, nl Ͻ 7), at LT Healthy (2 y, 8 mo after LT) 1939delA/IVS16-8TϾG (compound heterozygote) 647K then VFTSLX/ splice site disruption B/Female; Northern European Caucasian 0 Cholestasis from 2 wk, hospitalized for evaluation aged 12 wk None 28 mo, at open biopsy; AFP not determined Palliative care only; death aged 33 mo IVS18ϩ1GϾA/74CϾA (compound heterozygote) Splice site disruption/ S25X C/Male; Northern European Caucasian 0 Cholestasis from birth None 23 mo (AFP 30k, nl Ͻ 5; liver mass); histologic diagnosis at necropsy, 24 mo Palliative care only; death aged 24 mo 1445AϾG/3691CϾT (compound heterozygote) D482G/R1231W D/Male; Northern European Caucasian 1 Cholestasis from 3 wk Partial external biliary diversion (PEBD), 11 mo; decreased pruritus temporarily, clinical-laboratory test results and growth no better 22 mo (AFP 158k, nl Ͻ 15); liver mass; lung and bone lesions; chemotherapy given; histologic diagnosis at LT, 25 mo Death, 6 d after LT (sepsis; no HCC at necropsy) 890AϾG/890AϾG (homozygote) E297G/E297G E/Male; Northern European Caucasian 1 Growth failure from 6 mo; diagnosed 9.5 mo PEBD, 10 mo; no response 29 mo (incidental in explant; AFP 6.4k, nl Ͻ 9), at LT Healthy (5 y, 10 mo after LT) IVS7ϩ1GϾA/890AϾG (compound heterozygote) Splice site disruption/ E297G F/Male; Northern European Caucasian 1 Cholestasis from 6 wk None 16 mo (clinically unsuspected), at necropsy; AFP not determined Death with metastatic HCC in lungs IVS9ϩ1GϾT/not known Splice site disruption/ not known G/Female; Arabic 3 Cholestasis from 6 wk None 15 mo (AFP 11k, nl Ͻ 7; liver mass); histologic diagnosis at LT, 16 mo Healthy (1 y, 7 mo after LT) 1416TϾA/1416TϾA (homozygote) Y472X/Y472X H/Male; Northern European Caucasian 0 Evaluation at 6 mo for jaundice and growth failure PEBD, 32 mo; excellent response (pruritus resolved, bile salts in serum normal range, growth resumed) 52 mo (marked increase in abdominal size; tumor metastasized at diagnosis; AFP 2x106, nl Ͻ 9), at open biopsy Palliative care only; death 3 wk after diagnosis 890 AϾG/ IVS13del-13ˆ-8 (compound heterozygote) E297G/splice site disruption I/Male; Central Asian Caucasian 0 Cholestasis from birth None 13 mo (incidental in explant; AFP 831, nl Ͻ 23), at LT Healthy (1 y, 11 mo after LT) IVS19ϩ2TϾC (homozygote) Splice site disruption J/Male; Central Asian Caucasian 0 Cholestasis from 1 wk None 14 mo (AFP 4k, nl Ͻ 23; liver mass), at biopsy; confirmed at LT, 15 mo Healthy (1 y, 2 mo after LT) 2316TϾG (homozygote) Y772X K/Male; Northern European Caucasian 3 Cholestasis from 3 mo None 26 mo (marked increase in abdominal size; tumor metastasized at diagnosis; AFP not measured), at open biopsy Death with metastatic HCC in lungs, aged 27 mo None sought None predicted Fig. 1. Login to comment 138 ABCB11 p.Asp482Gly The common Polish mutation 1445AϾG (D482G)8 was present in one parent of a patient from whom leukocytes were not available (patient C). Login to comment 139 ABCB11 p.Glu297Gly The common European missense mutation 890AϾG (E297G)8 was present in 3 patients and their parents (patients D, E, and H). Login to comment 140 ABCB11 p.Glu297Gly Except for 890AϾG (E297G), none of the changes found was present in 500 control individuals representative of all major populations (University of California San Francisco Pharmacogenetics Project24; http://pharmacogenetics.ucsf.edu). Login to comment 177 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1231Trp Among the missense changes is 1 in exon 27 (patient C); those in patients D, E, and H (890AϾG [E297G], exon 9) and the other mutation in patient C (1445AϾG [D482G], exon 14) have been described previously.8 The 890AϾG (E297G) and 1445AϾG (D482G) mutations reportedly affect BSEP transport activity,21,33 with altered trafficking of BSEP to the canalicular membrane.33-35 The mutation in patient C, 3691CϾT (R1231W), is predicted to alter an amino acid residue between the ATP-binding cassette signature motif and the Walker B motif of BSEP. Login to comment 180 ABCB11 p.Arg1050Cys IVS18ϩ1GϾA, found in patient B, was (in combination with 3148CϾT [R1050C]) associated with "benign" recurrent intrahepatic cholestasis (BRIC)-namely, intrahepatic cholestasis with intermittent clinical manifestations (published as IVS19ϩ1GϾA through typographical error [L. Klomp, personal communication]).36 IVS16-8TϾG, found in patient A, has been associated with PFIC in several other patients. Login to comment 184 ABCB11 p.Arg1050Cys Of interest is the difference in phenotype between patient B, with PFIC in association with the genotype IVS18ϩ1GϾA / 74CϾA (S25X), and a patient with BRIC whose less severe disease was associated with the IVS18ϩ1GϾA / 3148CϾT (R1050C) genotype.24 Factors modulating penetrance of ABCB11 mutation have yet to be defined. Login to comment 185 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Also of interest is the presence among our patients of the 890AϾG (E297G) mutation (patient D, homozygous; patients E and H, heterozygous) and the 1445AϾG (D482G) mutation (patient C, heterozy- gous). Login to comment 187 ABCB11 p.Glu297Gly Our patients D, E, and H, all with 890AϾG (E297G) mutation, came to PEBD. Login to comment 218 ABCB11 p.Asp482Gly Note Added in Proof: The liver of yet another child with PFIC and hepatocellular carcinoma46 (3 years, 5 months of age at transplant hepatectomy) does not express BSEP; the common Polish mutation 1445AϾG(D482G)8 is present in one copy of ABCB11. Login to comment