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The molecular genetics of familial intrahepatic cholestasis
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  1. P L M JANSEN,
  2. M MÜLLER
  1. Department of Gastrointestinal and Liver Disease
  2. and Digestive Disease Research Centre
  3. University Hospital Groningen
  4. Groningen, Netherlands
  1. Professor P L M Jansen, Department of Gastroenterology, University Hospital Groningen, PO Box 30.001, 9700RB Groningen, Netherlands. Email: p.l.m.jansen{at}int.azg.nl

http://dx.doi.org/10.1136/gut.47.1.1

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    There is a growing list of genetic diseases caused by defects of one of the members of the ATP binding cassette (ABC) transporter superfamily.1 ABC transporters mediate the energy dependent transport of peptides, steroid hormones, and drugs and their metabolites across membranes, not only in mammals but also in fish, bacteria, worms, and even plants. ABC transporters are important in almost every human cell or organ and therefore the spectrum of diseases caused by defects of these proteins is diverse and includes: liver diseases (progressive familial intrahepatic cholestasis,2cystic fibrosis,3 Zellweger syndrome,4adrenoleuko- dystrophy,5 and Dubin-Johnson syndrome6); eye disorders (Stargardt disease,7 autosomal recessive retinitis pigmentosa,8 and cone-rod dystrophy9); disorders of cholesterol metabolism (familial HDL deficiency10 and Tangier disease10); and diseases of carbohydrate metabolism (familial persistent hyperinsulinaemic hypoglycaemia of infancy11).

    Progressive familial intrahepatic cholestasis type 1

    Progressive familial intrahepatic cholestasis (PFIC) belongs to a group of autosomal recessive diseases characterised by cholestasis starting in infancy (table 1). PFIC type 1 or Byler disease often begins with recurrent episodes of intrahepatic cholestasis progressing to permanent cholestasis with fibrosis, cirrhosis, and liver failure necessitating liver transplantation in the first decade of life.2 ,12-14 Children with PFIC are small for their age and, in addition to cholestasis and pruritus, they sometimes have diarrhoea, pancreatitis, and hearing loss.15 The larger bile ducts are anatomically normal and histologically the liver shows a picture of bland canalicular cholestasis without much bile duct proliferation, inflammation, fibrosis, or cirrhosis.14 ,16On electron microscopy there is a paucity of canalicular microvilli and a thickened pericanalicular network of microfilaments with coarse granular bile called “Byler bile” in the canaliculi. Characteristically serum gamma-glutamyltransferase (gamma-GT) activity is not increased or only slightly elevated while parameters of cholestasis such as alkaline phosphatase and serum primary bile acids (in particular chenodeoxycholic acid) are greatly increased. Serum cholesterol levels are usually normal.

    View this table:
    Table 1

    Genetic forms of intrahepatic cholestasis or hyperbilirubinaemia

    Many patients belong to the so-called Byler kindred: descendants of Jacob and Nancy Byler who emigrated in the late 18th century from Germany to the United States to become the founders of a large Amish kindred. Many patients outside the United States are unrelated to the Amish and the PFIC syndrome has been described in families in the Netherlands, Sweden, Greenland, and an Arab population.12-14 ,18 ,19 In the Amish and in some of the non-Amish families, the genetic defect was mapped to theFIC1 locus on chromosome 18q21-q22. ThisFIC1 locus was further characterised by detailed homozygosity mapping and gene scanning studies to a region encoding a member of a recently defined subfamily of P type ATPases (fig 1).

    Figure 1
    Figure 1

    Putative structure of FIC1. The FIC1 gene has been demonstrated to be mutated in patients with progressive familial intrahepatic cholestasis (PFIC) type 1 and benign recurrent intrahepatic cholestasis (BRIC).20 It encodes a membrane protein with 10 putative transmembrane domains that exhibits homology with proteins with presumed aminophospholipid translocase activity. The green boxes represent P type ATPase signature domains; the red symbols mark mutations.

    P type ATPases are not ABC transporters; they belong to a large family mainly encoding ion transport pumps such as Na+/K+ ATPase, Ca2+ ATPase, and the copper transporting Wilson protein ATP7B. The function of FIC1 is uncertain. Its homologue, the bovine P type ATPase II, appears to mediate the transport of aminophospholipids (that is phosphatidylserine) from the outer to the inner leaflet of plasma membranes.21 ,22 However, the debate about this protein continues.23 In humans, FIC1 is highly expressed in the pancreas, small intestine, urinary bladder, stomach, and prostate. This may explain the increased frequency of diarrhoea and pancreatitis in these patients but the relation with cholestasis, the hallmark of the disease, is not immediately apparent. For example, in the liver the protein is not highly expressed and is located in cholangiocytes, not in hepatocytes (see Mutero and colleagues24). Therefore, the relation between the FIC1 locus and cholestasis is unclear.

    Recurrent familial intrahepatic cholestasis

    Recurrent familial intrahepatic cholestasis is a term recently coined by Tygstrup and colleagues.25 This disease is also known as benign recurrent intrahepatic cholestasis (BRIC) or Summerskill syndrome and was described by Summerskill and Walshe in 1959.26 Despite recurrent attacks of cholestasis there is no progression to chronic liver disease. During the attacks patients are severely jaundiced and have pruritus, steatorrhoea, and weight loss. As in PFIC 1, serum gamma-GT is not elevated. Some patients also have renal stones, pancreatitis, and diabetes.25 Tygstrup and colleagues proposed dropping the adjective “benign” from the name of this disease because sometimes the cholestatic episodes interfere so much with the social life of these patients that transplantation is warranted.

    The gene involved in recurrent familial intrahepatic cholestasis has been mapped to the FIC1locus.20 ,27 ,28 This suggests that recurrent and progressive familial intrahepatic cholestasis type I are genetically and perhaps also pathophysiologically related.

    Progressive familial intrahepatic cholestasis type 2

    Genetic studies revealed that the FIC1locus was not involved in all patients with a PFIC type 1 phenotype and low serum gamma-GT.13 ,14 In a number of patients the disease was mapped to a locus on chromosome 2q24 which later proved to be the BSEP (bile salt export pump) gene.29-31 This gene encodes the canalicular bile salts export pump, a P-glycoprotein belonging to class B of the ABC transporter superfamily (for classification and overview of all known members of the ABC transporter superfamily seehttp://www.med.rug.nl/mdl/humanabc.htm). This protein was originally called “sister of P-glycoprotein”.32 ,33 Similar proteins in pigs, rats, and mice have a great degree of homology with human BSEP and antibodies directed against sequences at the carboxy terminus display cross species reactivity. This enabled localisation studies and it became clear that this protein is liver specific and is located in the canalicular domain of the plasma membrane of the hepatocyte. In a recent collaborative study we showed that in patients with PFIC type 2, canalicular staining with specific BSEP antibodies was negative and that all of these patients carry mutations in theBSEP gene34 (fig 2). As in PFIC type 1, serum gamma-GT activity in these patients is not elevated and bile duct proliferation is absent. However, there are also some differences from PFIC type 1: in PFIC 2 the disease frequently starts as non-specific giant cell hepatitis which is indistinguishable from idiopathic neonatal giant cell hepatitis; patients are usually permanently jaundiced and the disease rapidly progresses to persistent and progressive cholestasis requiring liver transplantation. Histologically the liver shows more inflammatory activity, giant cell transformation, and lobular and portal fibrosis than in PFIC.2 ,14 ,35 The bile of PFIC type 2 patients is amorphous or filamentous on electron microscopy. Extrahepatic manifestations are uncommon. PFIC type 2 patients do not respond to ursodeoxycholic acid therapy, in fact administration of ursodeoxycholic acid to some of these patients caused very high serum bile acid levels (>1 mmol/l) without any increase in biliary bile acid secretion.34 This is additional proof that the primary defect in these patients is a defective canalicular bile acid transport pump (fig 3).

    Figure 2
    Figure 2

    Putative structure of BSEP. The BSEP (bile salt export pump) gene has been demonstrated to be mutated in patients with progressive familial intrahepatic cholestasis (PFIC) type 2.31 ,32 It encodes a membrane protein with 12 putative transmembrane domains that functions as a major bile salt export pump.32 ,33 The white boxes represent the Walker A and B motifs and the “ABC” signature; the red symbols mark mutations (modified after Strautnieks and colleagues31).

    Figure 3
    Figure 3

    Bile salt transport. (A) Bile salts are taken up from the blood into the hepatocyte via carrier proteins in the basolateral membrane. These are NTCP or “sodium taurocholate cotransporting protein” and OATP or “organic anion transporting protein”. At the canalicular membrane bile salts are transported into the bile canaliculus by the ATP dependent “bile salt export pump” (BSEP). Hepatocanalicular transport of phospholipids, mainly phosphatidylcholine, is mediated by the P-glycoprotein MDR3. (B) In patients with progressive familial intrahepatic cholestasis type 2, BSEP is not expressed.

    Bile acids are not completely absent in the bile of these patients. Multidrug resistance protein 2 (MRP2 or canalicular multispecific organic anion transporter (cMOAT)), the canalicular transporter of bilirubin and other organic anions,35-37 also transports glucuronidated or sulphated bile acids.38 This transporter may act as an escape pathway under conditions of cholestasis. This may also explain why these patients are jaundiced despite an intact bilirubin transporter: bilirubin transport may be competitively inhibited by bile acid conjugates.

    Bile acid synthesis defects

    Defects of bile acid synthesis may resemble PFIC type 2. Claytonet al and Setchell et al described a defect in 3β-Δ5-C27-hydroxysteroid oxidoreductase as a cause of giant cell hepatitis,39 a condition also frequently seen at the onset of PFIC type 2. Deficiency of Δ4–3-oxosteroid-5β reductase and 3β-hydroxy C27steroid dehydrogenase/isomerase and mutations of the oxysterol 7alpha-hydroxylase gene (CYP7B1) may also be causes of neonatal hepatitis and cholestasis.40-42 In these diseases toxic intermediates are formed which cause cholestasis by interaction with the hepatic bile acid transporter.43 Bile acid synthesis defects are called PFIC type 4 by some authors.

    Progressive familial intrahepatic cholestasis type 3

    The third PFIC subtype, PFIC type 3, is quite different from the other PFIC subtypes. Serum gamma-GT activity is usually markedly elevated in these patients and the liver histology shows extensive bile duct proliferation, and portal and periportal fibrosis.44 ,45 Phenotypically PFIC type 3 resembles the mdr 2 −/− mice who have homozygous disruption of mdr2, a canalicular phospholipid translocator.46 In humans, mdr 2 is called MDR3 or P-glycoprotein 3 (PGY3) and the gene encoding this protein is mutated in this disease (fig 4).44 ,45 ,47MDR3/mdr2 acts as a flippase, moving phospholipids from the inner leaflet of the canalicular membrane to the outer leaflet which faces the canalicular lumen. In common with BSEP, MDR3/mdr2 is a P-glycoprotein belonging to class B of the ABC transporter superfamily.

    Figure 4
    Figure 4

    Putative structure of MDR3. The MDR3 gene has been demonstrated to be mutated in patients with progressive familial intrahepatic cholestasis (PFIC) type 3.44 ,45 ,47 It encodes a membrane protein with 12 putative transmembrane domains that functions as a phosphatidylcholine translocator. The white boxes represent the Walker A and B motifs and the “ABC” signature; the red symbols mark mutations.

    Phosphatidylcholine, the predominant phospholipid in bile, is washed down from the canalicular membrane into the bile by bile acids. Thus without bile acids, as in PFIC type 2, bile is devoid of phospholipids. Without MDR3, as in PFIC type 3, bile acid transport proceeds unimpaired. This has major consequences because in normal bile the inherent toxicity of bile acids is quenched by phosphatidylcholine. In the bile of PFIC 3 patients (and mdr 2 −/− mice) bile acid monomers are highly toxic to cholangiocytes and hepatocytes. In humans this is even more extreme than in mdr 2 −/− mice as the monohydroxy bile acids of humans are more toxic than the muricholic acids of mouse bile.

    In patients with PFIC type 3, symptoms present somewhat later in life than in PFIC types 1 and 2 and liver failure also occurs at a later age. Jaundice may be less apparent. Some of these patients respond to ursodeoxycholic acid therapy48 but liver transplantation is eventually often necessary.

    Mutations of the MDR3 gene on chromosome 7q21 is the underlying cause of the disease.44 ,45 ,47 Although PFIC 3 is discussed as a cholestatic disease, in a strictly physiological sense there is no cholestasis as bile flow is not impaired.46 The bile in these patients is toxic and this causes the cholestatic type of liver damage described above.

    Intrahepatic cholestasis of pregnancy

    Jacquemin et al reported a high incidence of intrahepatic cholestasis of pregnancy in one of their families with PFIC type 3.47 This suggests that in subjects carrying one mutated PGY3 gene, cholestasis may occur during pregnancy. Intrahepatic cholestasis of pregnancy has also been described in families with other PFIC subtypes.49-51

    Dubin-Johnson syndrome

    Dubin-Johnson syndrome is described here, not because it is an important cholestatic disease, but because it is caused by a mutation of an ABC transporter in the liver6 ,52-54 (fig 5). Dubin-Johnson syndrome is characterised by conjugated hyperbilirubinaemia without other serum enzyme abnormalities. Patients with Dubin-Johnson syndrome have a normal life span. A black or brownish lysosomal pigment in the hepatocytes is a characteristic histological feature and urinary coproporphyrin isomer I excretion is elevated.

    Figure 5
    Figure 5

    Putative structure of MRP2. The MRP2 gene has been demonstrated to be mutated in patients with Dubin-Johnson syndrome6 ,52-54 It encodes a membrane protein with 17 putative transmembrane domains that functions as a major export pump for anionic conjugates. The white boxes represent the Walker A and B motifs and the “ABC” signature; the red symbols mark mutations.

    The so-called TR− rat is an animal model for this disease. These animals have decreased hepatobiliary secretion of organic anions because of a mutation of the cmoat/mrp2gene.55-58 cMOAT, also called MRP2, is a member of the ABC transporter subfamily C of multidrug resistance associated proteins which includes CFTR, the cystic fibrosis transmembrane regulator, and SUR involved in familial persistent hyperinsulinaemic hypoglycaemia of infancy. Patients with the Dubin-Johnson syndrome are homozygous carriers ofcMOAT/MRP2 gene mutations.6 ,52-54

    Conclusion

    What do unlikely neighbours such as Stargardt disease, progressive familial intrahepatic cholestasis, and familial persistent hyperinsulinaemic hypoglycaemia of infancy have in common? They are all diseases caused by mutations of one of the members of the ABC transporter superfamily. Do these novel views provide any benefit for patients with these diseases? For most of the PFIC patients liver transplantation will remain necessary for some time to come but eventually gene therapy or transplantation of genetically corrected autologous hepatocytes may become a reality. Analysis of the aetiology of this heterogeneous group of Byler-like diseases has been a first and necessary step.

    Abbreviations used in this paper

    PFIC
    progressive familial intrahepatic cholestasis
    BRIC
    benign recurrent intrahepatic cholestasis
    gamma-GT
    gamma-glutamyltransferase
    BSEP
    bile salt export pump
    cMOAT
    canalicular multispecific organic anion transporter
    MRP2
    multidrug resistance protein 2
    PGY3
    P-glycoprotein 3
    ABC
    ATP binding cassette

    References

    1. ↵
      1. Allikmets R,
      2. Gerrard B,
      3. Hutchinson A,
      4. et al.
      (1996) Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 5:1649–1655.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Jacquemin E,
      2. Hadchouel M
      (1999) Genetic basis of progressive familial intrahepatic cholestasis. J Hepatol 31:377–381.
      OpenUrlCrossRefPubMed
    3. ↵
      1. Zielenski J,
      2. Tsui LC
      (1995) Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Gartner J,
      2. Moser H,
      3. Valle D
      (1992) Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. Nat Genet 1:16–23.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Mosser J,
      2. Lutz Y,
      3. Stoeckel ME,
      4. et al.
      (1994) The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet 3:265–271.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Kartenbeck J,
      2. Leuschner U,
      3. Mayer R,
      4. et al.
      (1996) Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061–1066.
      OpenUrlPubMedWeb of Science
    7. ↵
      1. Zhang K,
      2. Kniazeva M,
      3. Hutchinson A,
      4. et al.
      (1999) The ABCR gene in recessive and dominant stargardt diseases: a genetic pathway in macular degeneration. Genomics 60:234–237.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Cremers FP,
      2. van de Pol DJ,
      3. van Driel M,
      4. et al.
      (1998) Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum Mol Genet 7:355–362.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Shroyer NF,
      2. Lewis RA,
      3. Allikmets R,
      4. et al.
      (1999) The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial. Vision Res 39:2537–2544.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Brooks-Wilson A,
      2. Marcil M,
      3. Clee SM,
      4. et al.
      (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–345.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Thomas PM,
      2. Wohllk N,
      3. Huang E,
      4. et al.
      (1996) Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 59:510–518.
      OpenUrlPubMedWeb of Science
    12. ↵
      1. Bourke B,
      2. Goggin N,
      3. Walsh D,
      4. et al.
      (1996) Byler-like familial cholestasis in an extended kindred. Arch Dis Child 75:223–227.
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Arnell H,
      2. Nemeth A,
      3. Anneren G,
      4. et al.
      (1997) Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q22. Hum Genet 100:378–381.
      OpenUrlCrossRefPubMed
    14. ↵
      1. Bull LN,
      2. Carlton VE,
      3. Stricker NL,
      4. et al.
      (1997) Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease (PFIC-1) and Byler syndrome): evidence for heterogeneity. Hepatology 26:155–164.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Oshima T,
      2. Ikeda K,
      3. Takasaka T
      (1999) Sensorineural hearing loss associated with Byler disease. Tohoku J Exp Med 187:83–88.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Alonso EM,
      2. Snover DC,
      3. Montag A,
      4. et al.
      (1994) Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 18:128–133.
      OpenUrlPubMedWeb of Science
      1. Aagenaes Ø
      (1998) Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasis-lymphoedema syndrome). Scand J Gastroenterol 33:35–345.
      OpenUrl
    18. ↵
      1. Naveh Y,
      2. Bassan L,
      3. Rosenthal E,
      4. et al.
      (1997) Progressive familial intrahepatic cholestasis among the Arab population in Israel. J Pediatr Gastroenterol Nutr 24:548–554.
      OpenUrlCrossRefPubMed
    19. ↵
      1. Kagalwalla AF,
      2. Al Amir AR,
      3. Khalifa A,
      4. et al.
      (1995) Progressive familial intrahepatic cholestasis (Byler's disease) in Arab children. Ann Trop Paediatr 15:321–327.
      OpenUrlPubMed
    20. ↵
      1. Bull LN,
      2. van-Eijk MJ,
      3. Pawlikowska L,
      4. et al.
      (1998) A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 18:219–224.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Tang X,
      2. Halleck MS,
      3. Schlegel RA,
      4. et al.
      (1996) A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272:1495–1497.
      OpenUrlAbstract
    22. ↵
      1. Zhao J,
      2. Sims PJ,
      3. Wiedmer T
      (1997) Production and characterization of a mutant cell line defective in aminophospholipid translocase. Biochim Biophys Acta 1357:57–64.
      OpenUrlPubMed
    23. ↵
      1. Bevers EM,
      2. Comfurius P,
      3. Dellers DWC,
      4. et al.
      (1999) Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1439:317–330.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Mutero A,
      2. Bull LH,
      3. Pawlikowska L,
      4. et al.
      (1998) Cloning and tissue distribution of the rat homologue of the human gene involved in familial intrahepatic cholestasis type 1. Hepatology 28:530A.
      OpenUrlCrossRefWeb of Science
    25. ↵
      1. Tygstrup N,
      2. Steig BA,
      3. Juijn JA,
      4. et al.
      (1999) Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity. Hepatology 29:506–508.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Summerskill WHJ,
      2. Walshe JM
      (1959) Benign recurrent intrahepatic obstructive jaundice. Lancet 2:686–690.
      OpenUrlPubMedWeb of Science
    27. ↵
      1. Carlton VE,
      2. Knisely AS,
      3. Freimer NB
      (1995) Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region. Hum Mol Genet 4:1049–1053.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Bull LN,
      2. Juijn JA,
      3. Liao M,
      4. et al.
      (1999) Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Hum Genet 104:241–248.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Strautnieks SS,
      2. Kagalwalla AF,
      3. Tanner MS,
      4. et al.
      (1996) Locus heterogeneity in progressive familial intrahepatic cholestasis. J Med Genet 33:833–836.
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Strautnieks SS,
      2. Kagalwalla AF,
      3. Tanner MS,
      4. et al.
      (1997) Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet 61:630–633.
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Strautnieks SS,
      2. Bull LB,
      3. Kniseley AS,
      4. et al.
      (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20:233–238.
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Childs S,
      2. Yeh RL,
      3. Georges E,
      4. Ling V
      (1995) Identification of a sister gene to P-glycoprotein. Cancer Res 55:2029–2034.
      OpenUrlAbstract/FREE Full Text
    33. ↵
      1. Gerloff T,
      2. Stieger B,
      3. Hagenbuch B,
      4. et al.
      (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050.
      OpenUrlAbstract/FREE Full Text
    34. ↵
      1. Jansen PLM,
      2. Strautnieks SS,
      3. Jacquemin E,
      4. et al.
      (1999) Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 117:1370–1379.
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. Jedlitschky G,
      2. Leier I,
      3. Buchholz U,
      4. et al.
      (1997) ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochem J 327:305–310.
    36. ↵
      1. Keppler D,
      2. Leier I,
      3. Jedlitschky G
      (1997) Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biol Chem 378:787–791.
      OpenUrl
    37. ↵
      1. Kamisako T,
      2. Leier I,
      3. Cui Y,
      4. et al.
      (1999) Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 30:485–490.
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      1. Oude Elferink RPJ,
      2. de Haan J,
      3. Lamberts KJ,
      4. et al.
      (1989) Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect. Hepatology 9:861–865.
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      1. Clayton PT,
      2. Leonard JV,
      3. Lawson AM,
      4. et al.
      (1987) Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta,7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest 79:1031–1038.
    40. ↵
      1. Setchell KD,
      2. Suchy FJ,
      3. Welsh MB,
      4. et al.
      (1988) Delta 4–3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J Clin Invest 82:2148–2157.
    41. ↵
      1. Jacquemin E,
      2. Setchell KD,
      3. O'Connell NC,
      4. et al.
      (1994) A new cause of progressive intrahepatic cholestasis: 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency. J Pediatr 125:379–384.
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      1. Setchell KD,
      2. Schwarz M,
      3. O'Connell NC,
      4. et al.
      (1998) Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. J Clin Invest 102:1690–1703.
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      1. Stieger B,
      2. Zhang J,
      3. O'Neill B,
      4. et al.
      (1997) Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transporters. Eur J Biochem 244:39–44.
      OpenUrlPubMed
    44. ↵
      1. Deleuze JF,
      2. Jacquemin E,
      3. Dubuisson C,
      4. et al.
      (1996) Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 23:904–908.
      OpenUrlCrossRefPubMedWeb of Science
    45. ↵
      1. de Vree JM,
      2. Jacquemin E,
      3. Sturm E,
      4. et al.
      (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95:282–287.
      OpenUrlAbstract/FREE Full Text
    46. ↵
      1. Smit JJ,
      2. Schinkel AH,
      3. Oude Elferink R,
      4. et al.
      (1993) Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462.
      OpenUrlCrossRefPubMedWeb of Science
    47. ↵
      1. Jacquemin E,
      2. Cresteil D,
      3. Manouvrier S,
      4. et al.
      (1999) Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 353:210–211.
      OpenUrlCrossRefPubMedWeb of Science
    48. ↵
      1. Jacquemin E,
      2. Hermans D,
      3. Myara A,
      4. et al.
      (1997) Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 25:519–523.
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      1. Whitington PF,
      2. Freese DK,
      3. Alonso EM,
      4. et al.
      (1994) Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 18:134–141.
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      1. Clayton RJ,
      2. Iber FL,
      3. Ruebner BH,
      4. et al.
      (1969) Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 117:112–124.
      OpenUrlCrossRefPubMed
    51. ↵
      1. De Pagter AGF,
      2. van Berge Henegouwen GP,
      3. Ten Bokkel Huinink JA,
      4. et al.
      (1976) Familial benign recurrent intrahepatic cholestasis: Interrelation with intrahepatic cholestasis of pregnancy and oral contraceptives. Gastroenterology 71:202–207.
      OpenUrlPubMedWeb of Science
    52. ↵
      1. Paulusma CC,
      2. Kool M,
      3. Bosma PJ,
      4. et al.
      (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25:1539–1542.
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      1. Wada M,
      2. Toh S,
      3. Taniguchi K,
      4. et al.
      (1998) Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC-transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum Mol Genet 7:203–207.
      OpenUrlCrossRefPubMedWeb of Science
    54. ↵
      1. Tsuji H,
      2. König J,
      3. Rost D,
      4. et al.
      (1999) Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 117:653–660.
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      1. Jansen PLM,
      2. Peters WH,
      3. Lamers WH
      (1985) Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 5:573–579.
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      1. Kitamura T,
      2. Alroy J,
      3. Gatmaitan Z,
      4. et al.
      (1992) Defective biliary excretion of epinephrine metabolites in mutant (TR–) rats: Relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Correidale sheep with an analogous excretory defect. Hepatology 15:1154–1159.
      OpenUrlCrossRefPubMed
    57. ↵
      1. Paulusma CC,
      2. Bosma PJ,
      3. Zaman GJ,
      4. et al.
      (1996) Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271:1126–1128.
      OpenUrlAbstract
    58. ↵
      1. Büchler M,
      2. König J,
      3. Brom M,
      4. et al.
      (1996) cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J Biol Chem 271:15091–15098.
      OpenUrlAbstract/FREE Full Text

    Footnotes

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