|Institutional Source||Beutler Lab|
|Gene Name||ATP-binding cassette, sub-family B (MDR/TAP), member 4|
|Synonyms||Pgy-2, Mdr2, Pgy2, mdr-2|
|Is this an essential gene?||Non essential (E-score: 0.000)|
|Stock #||P0014 (G1)|
|Chromosomal Location||8893717-8959231 bp(+) (GRCm38)|
|Type of Mutation||missense|
|DNA Base Change (assembly)||A to G at 8950083 bp|
|Amino Acid Change||Tyrosine to Cysteine at position 1017 (Y1017C)|
|Ref Sequence||ENSEMBL: ENSMUSP00000003717 (fasta)|
|Gene Model||predicted gene model for transcript(s): [ENSMUST00000003717]|
|Predicted Effect||probably benign
AA Change: Y1017C
PolyPhen 2 Score 0.009 (Sensitivity: 0.96; Specificity: 0.77)
AA Change: Y1017C
|Meta Mutation Damage Score||0.1917|
|Coding Region Coverage||
|Validation Efficiency||95% (100/105)|
|MGI Phenotype||Strain: 1857236
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for targeted mutations that inactivate the gene are unable to secrete phospholipids into bile, leading to progressive hepatic disease, with an end stage of 3 months. [provided by MGI curators]
|Allele List at MGI|
|Other mutations in this stock||
|Other mutations in Abcb4||
|Protein Function and Prediction|
ATP-binding cassette, subfamily B, member 4 [Abcb4; alternatively P-glycoprotein 3 (PGY3) or Multidrug resistance 3 (MDR3)] is a member of the ATP-binding cassette transporter protein family. Abcb4 facilitates the translocation of phosphatidylcholine to the inner leaflet of the membrane (1).
either: (involves: 129P2/OlaHsd) or (involves: 129P2/OlaHsd * FVB/N)
In this genetic background, this mouse exhibits reduced female fertility as well as bile duct inflammation, hepatic necrosis, dilated bile ducts, cholestasis, liver hemorrhage and abnormal bile secretion (7;8). This model had increased circulating bilirubin, alanine transaminase, and aspartate transaminase levels (8). Also, beginning at 4 to 6 months, mice develop hepatocellular carcinoma with necrosis, hemorrhage, and strong cytonuclear polymorphism unlike in wild-type mice (7).
In this genetic background, homozygous animals also exhibit abnormal bile composition as well as fecal acidic sterol levels are decreased 30% compared to in wild-type mice however, fecal neutral sterol levels are normal (9). This model also had increased circulating bilirubin, alanine transaminase, and aspartate transaminase levels (9).
involves: 129P2/OlaHsd * FVB
In this genetic background, this model also had increased circulating bilirubin, alanine transaminase, and aspartate transaminase levels (10). Furthermore, homozygous animals had abnormal lipid homeostasis, decreased intestinal cholesterol absorption, and decreased circulating cholesterol levels (10).
1. Ruetz, S., and Gros, P. (1994) Phosphatidylcholine Translocase: A Physiological Role for the mdr2 Gene. Cell. 77, 1071-1081.
2. Bacq, Y., Gendrot, C., Perrotin, F., Lefrou, L., Chretien, S., Vie-Buret, V., Brechot, M. C., and Andres, C. R. (2009) ABCB4 Gene Mutations and Single-Nucleotide Polymorphisms in Women with Intrahepatic Cholestasis of Pregnancy. J Med Genet. 46, 711-715.
3. de Vree, J. M., Jacquemin, E., Sturm, E., Cresteil, D., Bosma, P. J., Aten, J., Deleuze, J. F., Desrochers, M., Burdelski, M., Bernard, O., Oude Elferink, R. P., and Hadchouel, M. (1998) Mutations in the MDR3 Gene Cause Progressive Familial Intrahepatic Cholestasis. Proc Natl Acad Sci U S A. 95, 282-287.
4. Deleuze, J. F., Jacquemin, E., Dubuisson, C., Cresteil, D., Dumont, M., Erlinger, S., Bernard, O., and Hadchouel, M. (1996) Defect of Multidrug-Resistance 3 Gene Expression in a Subtype of Progressive Familial Intrahepatic Cholestasis. Hepatology. 23, 904-908.
5. Degiorgio, D., Colombo, C., Seia, M., Porcaro, L., Costantino, L., Zazzeron, L., Bordo, D., and Coviello, D. A. (2007) Molecular Characterization and Structural Implications of 25 New ABCB4 Mutations in Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3). Eur J Hum Genet. 15, 1230-1238.
6. Rosmorduc, O., Hermelin, B., and Poupon, R. (2001) MDR3 Gene Defect in Adults with Symptomatic Intrahepatic and Gallbladder Cholesterol Cholelithiasis. Gastroenterology. 120, 1459-1467.
7. Mauad, T. H., van Nieuwkerk, C. M., Dingemans, K. P., Smit, J. J., Schinkel, A. H., Notenboom, R. G., van den Bergh Weerman, M. A., Verkruisen, R. P., Groen, A. K., and Oude Elferink, R. P. (1994) Mice with Homozygous Disruption of the mdr2 P-Glycoprotein Gene. A Novel Animal Model for Studies of Nonsuppurative Inflammatory Cholangitis and Hepatocarcinogenesis. Am J Pathol. 145, 1237-1245.
8. Smit, J. J., Schinkel, A. H., Oude Elferink, R. P., Groen, A. K., Wagenaar, E., van Deemter, L., Mol, C. A., Ottenhoff, R., van der Lugt, N. M., and van Roon, M. A. (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.
9. Langheim, S., Yu, L., von Bergmann, K., Lutjohann, D., Xu, F., Hobbs, H. H., and Cohen, J. C. (2005) ABCG5 and ABCG8 Require MDR2 for Secretion of Cholesterol into Bile. J Lipid Res. 46, 1732-1738.
|Science Writer||Anne Murray|