Abstract
BackgroundIntrahepatic cholestasis of pregnancy (ICP) can cause premature delivery and stillbirth. Previous studies have reported that mutations in ABC transporter genes strongly influence the transport of bile salts. However, to date, their effects are still largely elusive.MethodsA whole-exome sequencing (WES) approach was used to detect novel variants. Rare novel exonic variants (minor allele frequencies: MAF < 1%) were analyzed. Three web-available tools, namely, SIFT, Mutation Taster and FATHMM, were used to predict protein damage. Protein structure modeling and comparisons between reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively.ResultsWe detected a total of 2953 mutations in 44 ABC family transporter genes. When the MAF of loci was controlled in all databases at less than 0.01, 320 mutations were reserved for further analysis. Among these mutations, 42 were novel. We classified these loci into four groups (the damaging, probably damaging, possibly damaging, and neutral groups) according to the prediction results, of which 7 novel possible pathogenic mutations were identified that were located in known functional genes, including ABCB4 (Trp708Ter, Gly527Glu and Lys386Glu), ABCB11 (Gln1194Ter, Gln605Pro and Leu589Met) and ABCC2 (Ser1342Tyr), in the damaging group. New mutations in the first two genes were reported in our recent article. In addition, compared to the wild-type protein structure, the ABCC2 Ser1342Tyr-modified protein structure showed a slight change in the chemical bond lengths of ATP ligand-binding amino acid side chains. In placental tissue, the expression level of the ABCC2 gene in patients with ICP was significantly higher (P < 0.05) than that in healthy pregnant women. In particular, the patients with two mutations in ABC family genes had higher average values of total bile acids (TBA), aspartate transaminase (AST), direct bilirubin (DBIL), total cholesterol (CHOL), triglycerides (TG) and high-density lipoprotein (HDL) than the patients who had one mutation, no mutation in ABC genes and local controls.ConclusionsOur present study provide new insight into the genetic architecture of ICP and will benefit the final identification of the underlying mutations.
Highlights
Intrahepatic cholestasis of pregnancy (ICP) can cause premature delivery and stillbirth
We identified 2953 genetic variants, including 1254 mutations in 12 ABCA genes that consisted of ABCA1-ABCA10 and ABCA12ABCA13, 479 variants in ABCB1 and ABCB4-ABCB11, 812 genetic variants in eleven genes covering ABCC1ABCC6 and ABCC8-ABCC12, and 408 variants in the ABCD-ABCG gene series
The damage group had fifteen mutations, which contained six mutations in three known functional genes associated with ICP disease, such as ABCB4 Trp708Ter, Gly527Glu and Lys386Glu and ABCB11 Gln1194Ter, Gln605Pro and Leu589Met
Summary
Intrahepatic cholestasis of pregnancy (ICP) can cause premature delivery and stillbirth. Previous studies have reported that mutations in ABC transporter genes strongly influence the transport of bile salts. To date, their effects are still largely elusive. Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific liver disease characterized by pruritus and abnormal liver function, such as elevated liver enzymes and increased serum total bile acids (TBA) (≥ 10 μmol/L), that appears in the second and third trimesters of pregnancy and resolves completely after delivery in the early postpartum period [1]. It has been noted that approximately 2–4% of ICP pregnancies are affected by fetal mortality [9, 10]. Untangling the mechanisms of ICP and its association with fetal complications is very important
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