Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

Abstract

Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

Examining the key genes and pathways in hepatocellular carcinoma development from hepatitis B virus‑positive cirrhosis

“…Similarly, Sze et al ( 22 ) suggested that MAD2 deficiency may cause a mitotic checkpoint defect in hepatoma cells. Wills et al ( 23 ) suggested that BUB1, a loss-of-heterozygosity driver gene, may be implicated in the germline causes of genetic instability in polycystic liver disease. Furthermore, Wang et al ( 24 ) identified that BUB1B activated parathyroid hormone like hormone to promote the G-protein-coupled receptor-induced loss of cell adhesion.…”

Disease modelling in human organoids

“…Since these seminal papers, altered protocols have enabled the establishment of liver models from different species from rat to dog (Nantasanti et al, 2015; Kuijk et al, 2016; Kruitwagen et al, 2017), as well as human disease models ranging from alpha-1-antitrypsin (A1AT) deficiency and Alagille syndrome (Huch et al, 2015) to polycystic liver disease (Wills et al, 2016) or cancer (Broutier et al, 2017; Nuciforo et al, 2018). By modifying the Huch conditions to expand human organoids (Huch et al, 2015), the Vallier lab has recently established extrahepatic biliary organoids and showed that these can form bile-duct-like tubes that can reconstruct the gallbladder wall upon transplantation into mice (Sampaziotis et al, 2017a).…”

An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease

“…Based on previous studies showing that cystic cholangiocytes in polycystic liver disease have abnormal cell cycle profiles and malfunctioning cilia, Gradilone and collaborators (9) studied the role of HDAC6 in polycystic liver disease (PLD), which targets the epithelial lining of the biliary tree (41). They found that expression of the HDAC6 protein is six times higher in cystic liver tissue and in cultured cholangiocytes isolated from both PCK rats (an animal model of PLD) and humans with PLD.…”