Loss of heterozygosity in liver cysts of autosomal dominant polycystic liver disease (PCLD) depends on germline mutation of the patient

Background and Aims: Autosomal dominant polycystic liver disease (PCLD) is an inherited disorder characterised by a massive increase in liver volume due to multiple fluid filled cysts. Heterozygous germline PRKCSH and SEC63 gene mutations cause PCLD and lead to clinically identical phenotypes. There is loss of heterozygosity of PRKCSH in ∼80% of cyst epithelial cells from PRKCSH mutant patients. Here, we determined whether a similar mechanism is involved in cyst formation in SEC63 mutant patients. Methods: We collected freshly frozen liver tissue from 2 female PCLD patients with a heterozygous SEC63 c.1702-1704delGAA germline mutation. We collected between 300 and 800 cyst epithelial cells from 23 liver cysts through laser micro dissection in order to isolate cyst DNA. We used DNA from whole blood and laser dissected hepatocytes as control samples. The loss of heterozygosity status was determined using site specific PCR and sequencing. Results: We sequenced exon 17 from SEC63 in all DNA samples available. This demonstrated that the SEC63 germline mutation c.1702-1704delGAA was present in a heterozygous state in DNA isolated from whole blood, control hepatocytes, and laser dissected cyst epithelium. There was no loss of SEC63 heterozygosity in any of the 23 cyst epithelial samples. Conclusions: These results imply that the molecular mechanism controlling hepatic cyst formation depends on the genetic Background of the patient. While there is loss of heterozygosity in the majority of cysts from PRKCSH mutant patients, this is not the case in SEC63 mutant patients. This suggests that, at the genetic level, liver cyst formation is differently controlled in SEC63 mutant patients.