Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease.
Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation.
Interestingly, recent genetic work has linked mutations in the human and murine SIL1 genes to neurodegeneration, and mutations in the human SEC63 gene to autosomal dominant polycystic liver disease.
Polycystic livers are found in autosomal dominant polycystic kidney disease (ADPKD), caused by polycystic kidney disease (PKD)1 and PKD2 mutations in virtually all cases, and in isolated polycystic liver disease (PCLD), where 20% of cases are caused by mutations in Protein kinase C substrate 80K-H (PRKCSH) or SEC63.
Autosomal dominant polycystic liver disease (PCLD) is caused by mutations of either PRKCSH or Sec63, two proteins associated with the endoplasmic reticulum (ER).
In conclusion, we propose that, on the basis of our results, genetic screening for PRKCSH gene mutations should be limited to patients either with a positive family history for PCLD or who have severe polycystic liver disease.
Polycystic livers are found in autosomal dominant polycystic kidney disease (ADPKD), caused by polycystic kidney disease (PKD)1 and PKD2 mutations in virtually all cases, and in isolated polycystic liver disease (PCLD), where 20% of cases are caused by mutations in Protein kinase C substrate 80K-H (PRKCSH) or SEC63.
The 1338-2A-->G truncating mutation in hepatocystin observed in some polycystic liver disease patients produces a protein that is not retained in the endoplasmic reticulum but is secreted into the medium.
Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease).
Together, our analyses of sec63 mutant zebrafish highlight the possible role of ER stress in polycystic liver disease and suggest that these mutants will serve as a model for understanding the pathophysiology of this disease and other abnormalities involving ER stress.
In conclusion, as somatic second-hit mutations also play a role in cyst formation in patients with a SEC63 germline mutation, this appears to be a general mechanism of cyst formation in PCLD.
In conclusion, hepatocystin is not secreted in PCLD liver cyst fluid, suggesting that mutant hepatocystin is either not produced or degraded intracellularly.