ATP-binding cassette (ABC) transporter recessive mutations in biliary atresia cases

Abstract

Biliary atresia (BA) is an aggressive neonatal disorder characterized by progressive fibrosclerosing obliteration of the extrahepatic biliary tract in a few weeks after birth. Early surgical intervention by Kasai portoenterostomy to establish bile flow is critical to survival, yet disease progression to liver cirrhosis occurs in many patients, leaving liver transplantation the only option. BA has the highest prevalence of 1/5000 live births in the Southeast Asian population, 3 to 4 times higher than the US and European populations. Pathogenesis of BA remains uncertain. Consistent and robust evidence supporting theories of viral infection, immune dysregulation, environmental and multifactorial causes are yet to be established. Multiple genetic studies in different ethnic groups have identified ADD3 as a susceptibility gene of BA, yet disease-causal genetic risk factor is still in search. We conducted a whole exome sequencing study on 83 trios from the Southeast Asian population, and identified 148 rare non-synonymous de novo and inherited recessive mutations in 135 genes that were predicted to be damaging, and expressed in liver or bile duct tissues according to public databases and in-house BA liver organoid gene expression dataset. KEGG pathway analysis showed that ATP-binding cassette (ABC) transporter was significantly enriched (false discovery rate: 0.042), involving 4 genes (ABCA7, ABCA8, ABCC6, CFTR) with recessive variants in 4 subjects. In particular, recessive ABCA7 variants were carried by 2 BA subjects, one of which had 2 ABCA7 and a ABCC6 recessive mutations. In mice, Abcc6 deficiency causes altered gene expression of other bile salt and lipid transporters. ABCA7 is involved in lipid transport and plays an important role in lipid homeostasis. ABCA8 regulates lipid efflux, whereas CFTR regulates bile secretion at the apical membrane of biliary epithelial cells, and is associated with cystic fibrosis. Since altered bile acid metabolism can induce cholestatic liver injury, our initial findings warrant further functional studies on the specific functions of these ABC transporters in liver and biliary tissues, and their potential link with BA.