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A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults

Official URL:https://doi.org/10.1002/hep.22485
PubMed:View item in PubMed
Creators Name:Gotthardt, D. and Runz, H. and Keitel, V. and Fischer, C. and Flechtenmacher, C. and Wirtenberger, M. and Weiss, K.H. and Imparato, S. and Braun, A. and Hemminki, K. and Stremmel, W. and Rueschendorf, F. and Stiehl, A. and Kubitz, R. and Burwinkel, B. and Schirmacher, P. and Knisely, A.S. and Zschocke, J. and Sauer, P.
Journal Title:Hepatology
Journal Abbreviation:Hepatology
Volume:48
Number:4
Page Range:1157-1166
Date:October 2008
Keywords:Amino Acid Sequence, Bile Ducts, Cholestasis, Genotype, Liver, Biliary Liver Cirrhosis, Molecular Sequence Data, Missense Mutation, P-Glycoproteins, Pedigree, Phosphatidylcholines, Single Nucleotide Polymorphism, DNA Sequence Analysis, Severity of Illness Index
Abstract:Cholestatic liver disease (CLD) is a major cause of progressive liver damage and liver failure. Several forms of biliary cirrhosis are caused by mutations in specific genes. We sought to identify a genetic defect in a family with CLD impossible to assign to a distinct pathogenic entity. Clinical and histopathological characterization of the family members, microarray-based single-nucleotide polymorphism genotyping, and analysis of candidate genes were performed. Among six of 11 siblings severely affected by idiopathic CLD in a family from a population isolate in Transylvania, three died of cirrhosis (aged 5, 7, and 43 years) and three had adult-onset disease with small duct cholangiopathy, including ductopenia. Others were mildly affected and experienced intrahepatic cholestasis of pregnancy, miscarriages, or stillbirth. Pedigree studies revealed distant parental consanguinity. Genome-wide linkage analysis and autozygosity mapping yielded a single maximal lod-score of 3.88 on chromosome 7q21.1-7q22, excluding other genomic loci. Sequencing of ABCB4 at this locus revealed a novel missense mutation c.2362C>T (p.Arg788Trp) which cosegregated with severity of disease. Bile from a mutation homozygote showed a reduced phosphatidylcholine/bile acid ratio, consistent with reduced ABCB4 phosphatidylcholine transport activity. Conclusion: We show that a missense mutation in ABCB4 is a cause for ductopenic CLD in adulthood. Allelic status correlated with severity of liver disease ranging from intrahepatic cholestasis of pregnancy through fibrosis to cirrhosis and death in childhood and adulthood. Mutational analysis of ABCB4 should be generally considered in all patients with cholestatic liver disease of unknown etiology regardless of age and onset of disease.
ISSN:0270-9139
Publisher:Wiley (U.S.A.)
Item Type:Article

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