Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study

Abstract

Background 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. However, to date, their effects are still largely elusive. Methods A 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. Results We 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. Conclusions Our present study provide new insight into the genetic architecture of ICP and will benefit the final identification of the underlying mutations.

Manejo da colestase intra-hepática gestacional / Gestational intrahepatic cholestase management

“…Seu curso ocorre devido ao transporte anômalo de bile por meio da membrana canalicular, isso ocorre devido a comunhão de fatores genéticos, epigenéticos e endócrinos (decorrentes da própria gestação) (5) . No que concerne os fatores genéticos, as mutações dos genes ABCB11, ABCB4, ABCC2, ATP8B1 e receptor farnesoide X (FXR) são os principais causadores deste agravo, encontrados em até 15% das pacientes portadoras de CIHG.…”

“…No que concerne os fatores genéticos, as mutações dos genes ABCB11, ABCB4, ABCC2, ATP8B1 e receptor farnesoide X (FXR) são os principais causadores deste agravo, encontrados em até 15% das pacientes portadoras de CIHG. Estas mutações culminam em susceptibilidade ao estrogênio e a progesterona que inibem a bomba exportadora de sais biliares dos hepatócitos (5)(6)(7) .…”

“…Portanto, a forma mais eficaz de lidar com essa entidade patológica é seu rastreio e diagnóstico precoce, que são realizados por meio das consultas pré-natais. Isso deve ser realizado de forma a acompanhar clinicamente e laboratorialmente a gestante e, em casos de maior gravidade, antecipar o parto a fim de evitar desfechos fatais (3)(4)(5) . Logo, o estudo objetivou avaliar os aspectos fisiopatológicos e clínicos da CIHG, bem como seus efeitos sobre o feto.…”

Effect of intrahepatic cholestasis of pregnancy on infantile food allergy: A retrospective longitudinal study cohort in Southwest China

“…Intrahepatic cholestasis of pregnancy is the most common pregnancy specific liver disease, which classically presents in the third trimester with itching, typically of the palms and soles, abnormal liver function, and raised serum total bile acid levels [1][2][3][4][5]. The symptoms and biochemical abnormalities resolve rapidly after delivery [6,7].…”

Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients

“…To date, several bile acid homeostasis-related genes, including NR1H4 , ATP Binding Cassette Subfamily B Member 4 ( ABCB4 ), ATP Binding Cassette Subfamily B Member 11 ( ABCB11 ) and ATP Binding Cassette Subfamily C Member 2 ( ABCC2 ), have been reported. Moreover, multiple previous studies have identified genetic variants of the NR1H4 , ABCB4 , ABCB11 and ABCC2 genes that contribute to the development of ICP [ 15 – 20 ]. Among them, NR1H4 plays a central role in regulating bile acid metabolism.…”