X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C

Proc Natl Acad Sci U S A. 2011 May 10;108(19):7890-5. doi: 10.1073/pnas.1104631108. Epub 2011 Apr 25.


Transporters at the hepatic canalicular membrane are essential for the formation of bile and the prevention of cholestatic liver disease. One such example is ATP8B1, a P4-type ATPase disrupted in three inherited forms of intrahepatic cholestasis. Mutation of the X-linked mouse gene Atp11c, which encodes a paralogous P4-type ATPase, precludes B-cell development in the adult bone marrow, but also causes hyperbilirubinemia. Here we explore this hyperbilirubinemia in two independent Atp11c mutant mouse lines, and find that it originates from an effect on nonhematopoietic cells. Liver function tests and histology revealed only minor pathology, although cholic acid was elevated in the serum of mutant mice, and became toxic to mutant mice when given as a dietary supplement. The majority of homozygous mutant females also died of dystocia in a maternal genotype-specific manner. ATP11C therefore represents a multifunctional transporter, essential for adult B-cell development, the prevention of intrahepatic cholestasis, and parturition, and is a new candidate for genetically undiagnosed cases of cholestasis and dystocia in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology
  • Base Sequence
  • Cholestasis, Intrahepatic / enzymology*
  • Cholestasis, Intrahepatic / genetics*
  • Cholestasis, Intrahepatic / pathology
  • Cholic Acid / administration & dosage
  • Cholic Acid / toxicity
  • DNA Primers / genetics
  • Disease Models, Animal
  • Dystocia / enzymology
  • Dystocia / genetics
  • Female
  • Genes, X-Linked
  • Genetic Diseases, X-Linked / enzymology*
  • Genetic Diseases, X-Linked / genetics*
  • Homozygote
  • Hyperbilirubinemia, Hereditary / enzymology
  • Hyperbilirubinemia, Hereditary / genetics
  • Lymphopenia / enzymology
  • Lymphopenia / genetics
  • Lymphopenia / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Mitochondrial Proton-Translocating ATPases / physiology
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / physiology
  • Mutation*
  • Phenotype
  • Pregnancy


  • Atpaf1 protein, mouse
  • DNA Primers
  • Molecular Chaperones
  • Mitochondrial Proton-Translocating ATPases
  • Cholic Acid