Investigation of Common Variations of ABCB4, ATP8B1 and ABCB11 Genes in Patients with Progressive Familial Intrahepatic Cholestasis

Abstract

Background: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of hepatic disorders that can progress rapidly, leading to cirrhosis and death due to liver failure. Mutations and variations in three genes, including ATP8B1, ABCB11, and ABCB4, have been reported to be the main genetic cause of three subtypes of this disorder including PFIC1, PFIC2, and PFIC3, respectively. Objectives: Therefore, the aim of this study was to investigate more common mutations and variations associated with PFIC considering clinical and Para-clinical features of the disease. Methods: Thirty-five unrelated patients with PFIC from the south of Iran were selected randomly among all PFIC patients referring to Namazi hospital, affiliated to Shiraz University of Medical Sciences. Genomic DNA was extracted from the peripheral blood lymphocytes. Sequences related to these variations were then amplified by PCR in the 35 cholestasis patients and analyzed by Sanger® sequencing.

The role of p.Val444Ala variant in the ABCB11 gene and susceptibility to biliary atresia in Vietnamese patients

“…However, to date, no studies have been performed to evaluate the role of this variant in the susceptibility to BA. Publications have been done in patients with cholestasis, especially in PFIC [19–21] …”

“…Publications have been done in patients with cholestasis, especially in PFIC. [19][20][21] In this study, we selected the patients who were confirmed with BA by Kasai surgery and liver biopsy for genotype analysis. We performed whole exome sequencing of several patients with BA to identify the variants that might be the cause of the disease.…”

“…Defects in BSEP synthesis and/or function lead to reduced bile salt secretion and accumulation of bile salts. Based on the existing knowledge, a few studies have worked on the potential role of plasma bile acid levels and the contribution of variant p.Val444Ala (c.1331T>C, rs2287622) of ABCB11 to susceptibility for intrahepatic cholestasis of pregnancy and progressive familial intrahepatic cholestasis (PFIC) [19–21] . Sangkhathat et al [22] performed whole exome sequencing analysis in 20 BA patients and identified 13 rare variants in 9 genes that are associated with the disease: 4 in JAG1 (Alagille syndrome), 2 in MYO5B (PFIC type 6), and one each in ABCC2 (Dubin–Johnson syndrome), ABCB11 (PFIC type 2), UG1A1 (Crigler–Najjar syndrome), MLL2 (Kabuki syndrome), RFX6 (Mitchell–Riley syndrome), ERCC4 (Fanconi anemia), and KCNH1 (Zimmermann–Laband syndrome).…”