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Online mutation report
ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy
  1. R Müllenbach1,2,
  2. K J Linton2,
  3. S Wiltshire3,4,
  4. N Weerasekera2,
  5. J Chambers1,
  6. E Elias5,
  7. C F Higgins2,
  8. D G Johnston1,
  9. M I McCarthy2,3,4,
  10. C Williamson1,2
  1. 1Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
  2. 2MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
  3. 3Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
  4. 4Imperial College Genetics and Genomics Research Institute, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
  5. 5Department of Gastroenterology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK

    https://doi.org/10.1136/jmg.40.5.e70

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      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, …

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