ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a liver disease of pregnancy that complicates 0.7% of pregnancies in the UK.1,2 ICP causes maternal pruritus and hepatic impairment and can cause fetal death, spontaneous prematurity, and sudden intrauterine death.3–6 A diagnosis of ICP is made by the demonstration of abnormal liver function test results, and in particular the serum bile acids are raised.7–10 This is thought to be a consequence of abnormal bile transport across the hepatocyte canalicular membrane. Clinical features are heterogeneous and the aetiology is likely to be complex. Insights to the genetic aetiology of ICP have come from studies of the childhood liver disease progressive familial intrahepatic cholestasis (PFIC), a condition which is divided into three subtypes. Children with PFIC1 and 2 have low concentrations of biliary bile acids and low to normal gamma-glutamyl transpeptidase (GGT) in the serum. PFIC3 patients have high serum levels of GGT and bile which lacks phospholipid but has a normal biliary bile acid concentration.11 Homozygous mutations of the ABCB4 (also called MDR3 or mdr2 in the mouse) gene have been described in pedigrees with PFIC3.11–13 The ABCB4 protein is a member of the ATP binding cassette (ABC) family of membrane transporters.14–16 One of the normal functions of ABCB4 is to transport phosphatidylcholine across the hepatocyte canalicular membrane. The fact that expression is not only found in hepatocytes but also in B lymphocytes, heart, and muscle suggests that it may also transport other substrates. However, homozygous knockouts of the homologous (>90% identity at the amino acid level) murine mdr2 only had hepatic effects.17 Several heterozygous mothers of children with PFIC3 have symptoms consistent with ICP.11–13 In a large consanguineous pedigree with coexisting PFIC3 and ICP, …

[1]  T. Laatikainen,et al.  Serum Bile Acids in Cholestasis of Pregnancy , 1977, Obstetrics and gynecology.

[2]  S. Saarikoski,et al.  Risk of obstetric cholestasis in sisters of index patients , 2001, Clinical genetics.

[3]  Michael J. Hartshorn,et al.  Structural model of ATP-binding proteing associated with cystic fibrosis, multidrug resistance and bacterial transport , 1990, Nature.

[4]  I. J. Evans,et al.  A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria , 1986, Nature.

[5]  M. Hadchouel,et al.  Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy , 1999, The Lancet.

[6]  A. Shennan,et al.  Obstetric cholestasis, outcome with active management: a series of 70 cases , 2002, BJOG : an international journal of obstetrics and gynaecology.

[7]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[8]  J. Sjövall,et al.  Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158). , 1966, Clinica chimica acta; international journal of clinical chemistry.

[9]  O. Rosmorduc,et al.  MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. , 2001, Gastroenterology.

[10]  T. A. Kerr,et al.  Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. , 2000, Molecular cell.

[11]  W. Braun,et al.  Familial recurrent intrahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait. , 1983, Gastroenterology.

[12]  K. Linton,et al.  Cysteine‐scanning mutagenesis provides no evidence for the extracellular accessibility of the nucleotide‐binding domains of the multidrug resistance transporter P‐glycoprotein , 1999, The EMBO journal.

[13]  D. Clayton,et al.  A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. , 1999, American journal of human genetics.

[14]  E. Egginton,et al.  Intrahepatic cholestasis of pregnancy: prevalence and ethnic distribution. , 1999, Ethnicity & health.

[15]  P. Bosma,et al.  The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. , 2001, Gastroenterology.

[16]  B S Weir,et al.  Independence tests for VNTR alleles defined as quantile bins. , 1993, American journal of human genetics.

[17]  P. Sham,et al.  Model-Free Analysis and Permutation Tests for Allelic Associations , 1999, Human Heredity.

[18]  Y. Bacq,et al.  Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy. , 1995, Journal of hepatology.

[19]  P. Borst,et al.  Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease , 1993, Cell.

[20]  M. McCarthy,et al.  Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. , 2000, Human molecular genetics.

[21]  J. Girling,et al.  Liver function tests in pre‐eclampsia: importance of comparison with a reference range derived for normal pregnancy , 1997, British journal of obstetrics and gynaecology.

[22]  L. Moore,et al.  A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. , 2000, Molecular cell.

[23]  T. Laatikainen,et al.  Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy , 1984, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[24]  J. Parer,et al.  Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. , 1994, American journal of obstetrics and gynecology.

[25]  H. Reyes The Enigma of Intrahepatic Cholestasis of Pregnancy: Lessons from Chile , 2007, Hepatology.

[26]  N. Fisk,et al.  Fetal outcome in obstetric cholestasis , 1988, British journal of obstetrics and gynaecology.

[27]  P. Bosma,et al.  Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Makishima,et al.  The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. , 2001, Gastroenterology.

[29]  K. Ivey,et al.  Fetal complications of obstetric cholestasis. , 1976, British medical journal.

[30]  Jatinder Lamba,et al.  Disrupted Bile Acid Homeostasis Reveals an Unexpected Interaction among Nuclear Hormone Receptors, Transporters, and Cytochrome P450* , 2001, The Journal of Biological Chemistry.

[31]  C. Higgins,et al.  ABC transporters: from microorganisms to man. , 1992, Annual review of cell biology.