Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (115)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Dixon, P.H.
Right arrow Articles by Williamson, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dixon, P.H.
Right arrow Articles by Williamson, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2000, Vol. 9, No. 8 1209-1217
© 2000 Oxford University Press

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

P.H. Dixon1,2,+, N. Weerasekera1,2, K.J. Linton2, O. Donaldson1, J. Chambers1, E. Egginton3, J. Weaver4, C. Nelson-Piercy5, M. de Swiet6, G. Warnes2, E. Elias3, C.F. Higgins2, D.G. Johnston1, M.I. McCarthy1,2 and C. Williamson1,2,6,§

1Division of Medicine, Imperial College School of Medicine and 2MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK, 3Department of Gastroenterology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK, 4Department of Obstetrics and Gynaecology, Birmingham Women’s Hospital, Birmingham, B15 2TG, UK, 5Department of Obstetrics, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK and 6Institute of Obstetrics and Gynaecology, Queen Charlottes’ Hospital, Goldhawk Road, London W5 0XG, UK

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) with raised serum {gamma}-glutamyl transpeptidase ({gamma}-GT). Affected children have homozygous mutations in the MDR3 gene (also called ABCB4), and heterozygous mothers have ICP. More frequently, however, ICP occurs in women with no known family history of PFIC and the genetic basis of this disorder is unknown. We investigated eight women with ICP and raised serum {gamma}-GT, but with no known family history of PFIC. DNA sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3 in one patient, which results in the missense substitution of the wild-type alanine with an aspartic acid. We performed functional studies of this mutation introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated cell sorting (FACS) and western analysis indicated that this missense mutation causes disruption of protein trafficking with a subsequent lack of functional protein at the cell surface. The demonstration of a heterozygous missense mutation in the MDR3 gene in a patient with ICP with no known family history of PFIC, analysed by functional studies, is a novel finding. This shows that MDR3 mutations are responsible for the additional phenotype of ICP in a subgroup of women with raised {gamma}-GT.

+ Present address: Neurogenetics Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK

§ To whom correspondence should be addressed at: ICSM Maternal and Fetal Disease Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Tel: +44 208 383 3014; Fax: +44 208 383 8306; Email: catherine.williamson@ic.ac.uk


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Med. Genet.Home page
Y Bacq, C Gendrot, F Perrotin, L Lefrou, S Chretien, V Vie-Buret, M-C Brechot, and C R Andres
ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy
J. Med. Genet., October 1, 2009; 46(10): 711 - 715.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. J. Hoosdally, E. J. Andress, C. Wooding, C. A. Martin, and K. J. Linton
The Human Scavenger Receptor CD36: GLYCOSYLATION STATUS AND ITS ROLE IN TRAFFICKING AND FUNCTION
J. Biol. Chem., June 12, 2009; 284(24): 16277 - 16288.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
P H Dixon, S W C van Mil, J Chambers, S Strautnieks, R J Thompson, F Lammert, R Kubitz, V Keitel, A Glantz, L-A Mattsson, et al.
Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy
Gut, April 1, 2009; 58(4): 537 - 544.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
Y. J. Cui, X. Cheng, Y. M. Weaver, and C. D. Klaassen
Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a, Mdr1b, Mdr2) in Mice
Drug Metab. Dispos., January 1, 2009; 37(1): 203 - 210.
[Abstract] [Full Text] [PDF]

Home page
 Obstet MedHome page
P H Dixon and C Williamson
The molecular genetics of intrahepatic cholestasis of pregnancy
Obstet Med, December 1, 2008; 1(2): 65 - 71.
[Abstract] [Full Text] [PDF]

Home page
 PhysiologyHome page
J. J. Eloranta and G. A. Kullak-Ublick
The Role of FXR in Disorders of Bile Acid Homeostasis
Physiology, October 1, 2008; 23(5): 286 - 295.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
J. K. Zolnerciks, C. Wooding, and K. J. Linton
Evidence for a Sav1866-like architecture for the human multidrug transporter P-glycoprotein
FASEB J, December 1, 2007; 21(14): 3937 - 3948.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
H E Wasmuth, A Glantz, H Keppeler, E Simon, C Bartz, W Rath, L-A Mattsson, H-U Marschall, and F Lammert
Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene
Gut, February 1, 2007; 56(2): 265 - 270.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi
Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System.
Physiol Rev, October 1, 2006; 86(4): 1179 - 1236.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. Chan, G. Calderon, A. L. Swift, J. Moseley, S. Li, H. Hosoya, I. M. Arias, and D. F. Ortiz
Myosin II Regulatory Light Chain Is Required for Trafficking of Bile Salt Export Protein to the Apical Membrane in Madin-Darby Canine Kidney Cells
J. Biol. Chem., June 24, 2005; 280(25): 23741 - 23747.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
R Mullenbach, A Bennett, N Tetlow, N Patel, G Hamilton, F Cheng, J Chambers, R Howard, S D Taylor-Robinson, and C Williamson
ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy
Gut, June 1, 2005; 54(6): 829 - 834.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
S W C van Mil, R H J Houwen, and L W J Klomp
Genetics of familial intrahepatic cholestasis syndromes
J. Med. Genet., June 1, 2005; 42(6): 449 - 463.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Ropponen, K. Aittomaki, M. J. Tikkanen, and O. Ylikorkala
Levels of Serum C-Reactive Protein during Oral and Transdermal Estradiol in Postmenopausal Women with and without a History of Intrahepatic Cholestasis of Pregnancy
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 142 - 146.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. Shoda, Y. Inada, A. Tsuji, H. Kusama, T. Ueda, T. Ikegami, H. Suzuki, Y. Sugiyama, D. E. Cohen, and N. Tanaka
Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPAR{alpha}-mediated redistribution of ABCB4
J. Lipid Res., October 1, 2004; 45(10): 1813 - 1825.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. F. Ortiz, J. Moseley, G. Calderon, A. L. Swift, S. Li, and I. M. Arias
Identification of HAX-1 as a Protein That Binds Bile Salt Export Protein and Regulates Its Abundance in the Apical Membrane of Madin-Darby Canine Kidney Cells
J. Biol. Chem., July 30, 2004; 279(31): 32761 - 32770.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
R. R. Singaraja, L. R. Brunham, H. Visscher, J. J.P. Kastelein, and M. R. Hayden
Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene
Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1322 - 1332.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
M Savander, A Ropponen, K Avela, N Weerasekera, B Cormand, M-L Hirvioja, S Riikonen, O Ylikorkala, A-E Lehesjoki, C Williamson, et al.
Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy
Gut, July 1, 2003; 52(7): 1025 - 1029.
[Abstract] [Full Text]

Home page
 J. Med. Genet.Home page
R Mullenbach, K J Linton, S Wiltshire, N Weerasekera, J Chambers, E Elias, C F Higgins, D G Johnston, M I McCarthy, and C Williamson
ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy
J. Med. Genet., May 1, 2003; 40(5): e70 - 70.
[Full Text] [PDF]

Home page
 J. Med. Genet.Home page
C Gendrot, Y Bacq, M-C Brechot, J Lansac, and C Andres
A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy
J. Med. Genet., March 1, 2003; 40(3): e32 - 32.
[Full Text] [PDF]

Home page
 GutHome page
P Milkiewicz, A P Chilton, S G Hubscher, and E Elias
Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2)
Gut, February 1, 2003; 52(2): 300 - 303.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
P. Milkiewicz, E. Elias, C. Williamson, and J. Weaver
Obstetric cholestasis
BMJ, January 19, 2002; 324(7330): 123 - 124.
[Full Text] [PDF]

Home page
 Reproductive SciencesHome page
A. M. Germain, J. A. Carvajal, J. C. Glasinovic, S. K. C., and C. Williamson
Intrahepatic Cholestasis of Pregnancy: An Intriguing Pregnancy-Specific Disorder
Reproductive Sciences, January 1, 2002; 9(1): 10 - 14.
[Abstract] [PDF]

Home page
 J. Lipid Res.Home page
M. Dean, Y. Hamon, and G. Chimini
The human ATP-binding cassette (ABC) transporter superfamily
J. Lipid Res., July 1, 2001; 42(7): 1007 - 1017.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
M. Dean, A. Rzhetsky, and R. Allikmets
The Human ATP-Binding Cassette (ABC) Transporter Superfamily
Genome Res., July 1, 2001; 11(7): 1156 - 1166.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.