A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis

  title={A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis},
  author={Laura N. Bull and Michiel JT van Eijk and Ludmila Pawlikowska and Joseph A. Deyoung and Jenneke A. Juijn and M Liao and Leo W. J. Klomp and Nour-eddine Lomri and Ruud Berger and Bruce R. Scharschmidt and Alex S. Knisely and Roderick H. J. Houwen and Nelson B. Freimer},
  journal={Nature Genetics},
Cholestasis, or impaired bile flow, is an important but poorly understood manifestation of liver disease. Two clinically distinct forms of inherited cholestasis, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), were previously mapped to 18q21. Haplotype analysis narrowed the candidate region for both diseases to the same interval of less than 1 cM, in which we identified a gene mutated in BRIC and PFIC1 patients. This gene… 
Another form of familial intrahepatic cholestasis, another new genek
Data provide evidence that SPGP is the human bile transporter, sister of p-glycoprotein (SPGP), as well as investigating whether protein phosphatases 1 and 2A (PP1/2A) are involved in the regulation of Na 1 /TC cotransport by cAMP.
A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis
Data provide evidence that SPGP is the human bile salt export pump (BSEP), and the product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro.
Two novel ATP8B1 mutations involved in progressive familial intrahepatic cholestasis type 1 that is ameliorated by rifampicin: A case report
The genetic causes of PFIC1 and the carriers need to be identified for the early detection and prenatal diagnosis ofPFIC1, a group of inherited liver diseases characterized by defects in the transporters of the biliary epithelia.
New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications
The current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases are summarized and the therapeutic options are outlined, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C
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.
Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center
The results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission in familial intrahepatic cholestasis.
Liver disease without flipping: New functions of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1
A combined search for the two disease loci identified a P-type adenosine triphosphatase, ATPase class I type 8B member 1 (gene symbol, ATP8B1), as the defective gene for both PFIC1 and the type 1 form of BRIC.
Genetic cholestasis: lessons from the molecular physiology of bile formation.
  • P. Jansen, M. Müller
  • Medicine, Biology
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie
  • 2000
Intrahepatic cholestasis of pregnancy (ICP) appears to be related to these cholESTatic diseases, and heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in Families with BRIC.
A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators
These FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease are reviewed and suggest that defects in intracellular trafficking take a prominent place in FIC.
Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.
  • R. Wang, M. Salem, V. Ling
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
The knockout of spgp gene in mice results in intrahepatic cholestasis, but with significantly less severity than PFIC2 in humans, and mutant mice display a significant increase in the secretion of cholesterol and phospholipids into the bile.


Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.
A locus for progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, has been mapped to a 19 cM region of chromosome 18 by a search for shared segments, using patients from
Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
The results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum gamma-GT.
Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.
A locus designated "PFIC2" has been mapped to chromosome 2q24 by use of homozygosity mapping and a genome scan in six consanguineous PFIC pedigrees from the Middle East, indicating the existence of locus heterogeneity within the PFIC phenotype.
Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64
The linkage analysis of an expanded sample of 14 BRIC families is reported, using 15 microsatellite markers from the 18q21 region, and one family is identified in which the BRIC gene seems to be unlinked to the 18 QT20 region, or that represents incomplete penetrance of theBRIC genotype.
Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC‐1] and Byler syndrome): Evidence for heterogeneity
Examination of haplotypes in siblings with ByS in two unrelated non‐Amish families showed that the gene(s) responsible for their disorder did not lie in the PFIC‐1 candidate region, and genetic analysis and light microscopy and TEM of liver may help distinguish PF IC‐1 from other forms of ByS.
Byler-like familial cholestasis in an extended kindred.
Five children from two consanguineous marriages in an Irish kindred with a history of neonatal diarrhoea, sepsis, and intermittent jaundice suffer from a form of PFIC remarkably similar to that occurring in members of the Byler kindred.
Byler's disease: fatal intrahepatic cholestasis.
Byler Disease: Fatal Familial Intrahepatic Cholestasis in an Amish Kindred
Pedigree pattern and demonstration of biochemical abnormality in four presumed heterozygotes are evidence of the autosomal recessive nature of the syndrome.