An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy

Sci Rep. 2017 Sep 18;7(1):11823. doi: 10.1038/s41598-017-11626-x.

Abstract

Intrahepatic cholestasis of pregnancy (ICP) affects 1/140 UK pregnancies; with pruritus, hepatic impairment and elevated serum bile acids. Severe disease is complicated by spontaneous preterm delivery and stillbirth. Previous studies have reported mutations in hepatocellular transporters (ABCB4, ABCB11). High throughput sequencing in 147 patients was performed in the transporters ABCB4, ABCB11, ATP8B1, ABCC2 and tight junction protein 2 (TJP2). Twenty-six potentially damaging variants were identified with the following predicted protein changes: Twelve ABCB4 mutations - Arg47Gln, Met113Val, Glu161Gly, Thr175Ala, Glu528Glyfs*6, Arg590Gln, Ala601Ser, Glu884Ter, Gly722Ala, Tyr775Met (x2), Trp854Ter. Four potential ABCB11 mutations - Glu297Gly (x3) and a donor splice site mutation (intron 19). Five potential ATP8B1 mutations - Asn45Thr (x3), and two others, Glu114Gln and Lys203Glu. Two ABCC2 mutations - Glu1352Ala and a duplication (exons 24 and 25). Three potential mutations were identified in TJP2; Thr62Met (x2) and Thr626Ser. No patient harboured more than one mutation. All were heterozygous. An additional 545 cases were screened for the potential recurrent mutations of ATP8B1 (Asn45Thr) and TJP2 (Thr62Met) identifying three further occurrences of Asn45Thr. This study has expanded known mutations in ABCB4 and ABCB11 and identified roles in ICP for mutations in ATP8B1 and ABCC2. Possible novel mutations in TJP2 were also discovered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics*
  • Adenosine Triphosphatases / genetics*
  • Amino Acid Substitution
  • Cholestasis, Intrahepatic / genetics*
  • Female
  • Heterozygote*
  • Humans
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics*
  • Mutation, Missense*
  • Pregnancy
  • Pregnancy Complications / genetics*
  • Zonula Occludens-2 Protein / genetics*

Substances

  • ABCB11 protein, human
  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • TJP2 protein, human
  • Zonula Occludens-2 Protein
  • Adenosine Triphosphatases
  • ATP8B1 protein, human

Supplementary concepts

  • Intrahepatic Cholestasis of Pregnancy