An investigation of the Ciliary Protein PKHD1 in Cyst development in liver disease: clues to the pathogenesis of Biliary Atresia

Abstract

Biliary atresia is a common form of paediatric liver disease, with progressive, inflammatory obliteration of the biliary tree, leading to liver failure early in life. Mutations in PKHD1, encoding the ciliary protein fibrocystin, are associated with autosomal recessive polycystic kidney disease (ARPKD), a ciliopathy with clinical features that resemble biliary atresia. The hepatic developmental defects detectable in a significant number of infants with ARPKD are thought to be caused by dysfunction in the structure and function of primary cilia. The pathogenetic mechanism of both disorders is thought to be dysregulation of epithelial cell growth and tubulomorphogenesis. Preliminary investigations uncovered an association of PKHD1 sequence variants in a subset of biliary atresia patients with renal cysts, promoting further investigation to determine the functional role of fibrocystin in epithelial cells from renal and biliary tubules. Immunohistochemical studies, using a monoclonal antibody raised against wildtype fibrocystin, showed that it localises specifically to intrahepatic bile ducts. Absence of fibrocystin staining in end-stage liver tissue reflects ongoing damage to the intrahepatic biliary tree, rather than a phenomenon specific to biliary atresia. Studies utilising the Pkhd1 $^{del2/del2}$ mouse model of ARPKD revealed 17β-estradiol sensitive centrosomal overduplication underlies the dysregulation of epithelial cell growth in renal tubules, however this does not appear to be in synergy with $Pkhd1$ knockdown. Therefore, it remains uncertain whether sequence variants of PKHD1 are associated with biliary atresia