Intrahepatic bile duct primary cilia in biliary atresia

Abstract

The presence of IHBC in BA livers at the diagnosis was associated with resolution of cholestasis, although was not predictive of short-term survival with native liver. Scanning electron microscopy represents a powerful new tool to study routine liver biopsies in biliary disorders. Cilia dysfunction in BA pathogenesis and/or disease progression warrants further investigation.

Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism

“…The genetic contributions to cholangiocyte ciliary malformation and ciliary protein dysfunction appear to be heterogeneous, demonstrated by the diverse spectrum of liver expressed ciliary genes identified to carry RDL variants in BA cases in this study. We found almost a third of BA subjects with rare, damaging, liver expressed ciliary gene variants, whilst a previous descriptive histopathological study observed cilia abnormalities in 86% of BA subjects [49] . The considerable gap could be attributed to the ciliary gene list we applied is relatively conserved, including only genes from SYSCILIA gold standard and GO databases for a list of confident ciliary genes, but not the candidate genes in other databases where stronger evidence of their ciliary nature are yet to be established.…”

“…In different tissue types, aberrant or absent cilia, or mutations in IFT proteins were shown to cause Hh loss- or gain-of-function phenotypes [ 46 , 47 ]. Indeed, shorter, misoriented, or less abundant cholangiocyte cilia were commonly observed in several studies of both syndromic and nonsyndromic BA patients [48] , [49] , [50] , meanwhile Hh activity was shown to be associated with jaundice-free survival of BA patients in another study [51] . Our current study is the first to suggest genetic defects might underlie these observations in nonsyndromic patients.…”

Whole exome sequencing reveals a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia

“…The genetic contributions to cholangiocyte ciliary malformation and ciliary protein dysfunction appear to be heterogeneous, demonstrated by the diverse spectrum of liver expressed ciliary genes identified to carry predicted pathogenic variants in BA cases in this study, with scarce multiple occurrences observed for individual variants or genes. We found almost a third of BA subjects with rare, damaging, liver expressed ciliary gene variants, whilst a previous descriptive histopathological study observed cilia abnormalities in 86% of BA subjects (23). The considerable gap could be attributed to the ciliary gene list we applied is relatively conserved, including only genes from SYSCILIA gold standard and GO databases for a list of confident ciliary genes, and not candidate genes in other databases where stronger evidence of their ciliary nature are yet to be established.…”

“…In addition, it is likely that defective cilia would compromise the protective function of immature neonatal cholangiocytes against bile acid insults, leading to chronic liver injury, which can also hyperactivate Hh signalling. Indeed, shorter, misoriented, or less abundant cholangiocyte cilia were commonly observed in several studies of both syndromic and non-syndromic BA patients (22)(23)(24). Aberrant or absent cilia, or mutations in IFT proteins were shown to cause Hh loss-or gain-of-function phenotypes in different tissue types (25,26).…”

Cholangiopathies – Towards a molecular understanding

“…It will be interesting to explore how dysfunctional Notch signaling in ALGS links to the molecular programs setting up apical-basal polarity. Disruption of the primary cilia, a signaling center located at the apical side of cholangiocytes, leads to biliary fibrosis and macrophage infiltration in a mouse model for hepatorenal fibrocystic disease [ 63 ], and in line with this, reduction in the frequency of primary cilia has been observed in BA [ 64 ]. Similarly, a number of ciliopathies affect cholangiocyte and ductal plate differentiation [ 65 ].…”