Defective ABCB4 does not transport PC from plasma membrane to extracellular region

Stable Identifier
Reaction [transition]
Homo sapiens
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Multidrug resistance protein 3 (ATP-binding cassette sub-family B member 4, ABCB4 aka MDR3) mediates the ATP-dependent export of organic anions, phospholipids and drugs from hepatocytes into the canalicular lumen in the presence of bile salts, especially the export of phospholipids such as phosphatidylcholine (PC). Biliary phospholipids associate with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallisation. Thus, ABCB4 plays a crucial role in bile formation and lipid homeostasis.

Defects in ABCB4 result in a wide spectrum of cholestasis phenotypes, from progressive familial intrahepatic cholestasis 3 (PFIC3; MIM:602347), intrahepatic cholestasis of pregnancy 3 (ICP3; MIM:614972) to gallbladder disease 1 (GBD1; MIM:600803). Mutations causing PFIC3 include R957*, Y403H and V571Dfs*16 (de Vree et al. 1998, Degiorgio et al. 2007, Jacquemin et al. 1999). Mutations causing ICP3 include A546D, R144* and R590Q (Dixon et al. 2000, Bacq et al. 2009, Ziol et al. 2008). Mutations causing GBD1 include T175V, P1161S and R545G (Rosmorduc et al. 2001, Ziol et al. 2008).

Literature References
PubMed ID Title Journal Year
17726488 Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3)

Colombo, C, Seia, M, Zazzeron, L, Costantino, L, Porcaro, L, Degiorgio, D, Coviello, DA, Bordo, D

Eur. J. Hum. Genet. 2007
11313316 MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis

Hermelin, B, Rosmorduc, O, Poupon, R

Gastroenterology 2001
10767346 Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking

Donaldson, O, Linton, KJ, Higgins, CF, Chambers, J, de Swiet, M, McCarthy, MI, Nelson-Piercy, C, Egginton, E, Elias, E, Dixon, PH, Weaver, J, Johnston, DG, Warnes, G, Williamson, C, Weerasekera, N

Hum. Mol. Genet. 2000
9923886 Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy

Jacquemin, E, Manouvrier, S, Boute, O, Hadchouel, M, Cresteil, D

Lancet 1999
18482588 ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults

Hermelin, B, Bennouna, S, Frassati-Biaggi, A, Trinchet, JC, Ziol, M, Ganne-Carrié, N, Barbu, V, Barget, N, Beaugrand, M, Rosmorduc, O, Scheffer, GL

Gastroenterology 2008
19584064 ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy

Lefrou, L, Gendrot, C, Brechot, MC, Bacq, Y, Vie-Buret, V, Perrotin, F, Andres, CR, Chrétien, S

J. Med. Genet. 2009
9419367 Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis

Oude Elferink, RP, Burdelski, M, Jacquemin, E, Bernard, O, Desrochers, M, De Vree, JM, Aten, J, Bosma, PJ, Sturm, E, Hadchouel, M, Deleuze, JF, Cresteil, D

Proc. Natl. Acad. Sci. U.S.A. 1998
Catalyst Activity

phospholipid transporter activity of ABCB4 mutants [plasma membrane]

Normal reaction
Functional status

Loss of function of ABCB4 mutants [plasma membrane]

Name Identifier Synonyms
cholelithiasis DOID:10211
intrahepatic cholestasis DOID:1852 intrahepatic cholestasis of pregnancy
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