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


CONCLUSIONS
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.
Gotthardt
Daniel
D
Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany. daniel.gotthardt@med.uni-heidelberg.de
Runz
Heiko
H
Keitel
Verena
V
Fischer
Christine
C
Flechtenmacher
Christa
C
Wirtenberger
Michael
M
Weiss
Karl Heinz
KH
Imparato
Sandra
S
Braun
Annika
A
Hemminki
Kari
K
Stremmel
Wolfgang
W
Rüschendorf
Franz
F
Stiehl
Adolf
A
Kubitz
Ralf
R
Burwinkel
Barbara
B
Schirmacher
Peter
P
Knisely
A S
AS
Zschocke
Johannes
J
Sauer
Peter
P
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D001652:Bile Ducts / Q000002:abnormalities*; D002779:Cholestasis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010713:Phosphatidylcholines / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index
D018435:ATP Binding Cassette Transporter, Subfamily B; D010713:Phosphatidylcholines; C095122:multidrug resistance protein 3