Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant polycystic liver disease

MJ Janssen, E Waanders, RHM Te Morsche, R Xing… - Gastroenterology, 2011 - Elsevier
MJ Janssen, E Waanders, RHM Te Morsche, R Xing, HBPM Dijkman, J Woudenberg…
Gastroenterology, 2011Elsevier
BACKGROUND & AIMS: Heterozygous germline mutations in PRKCSH cause autosomal
dominant polycystic liver disease (PCLD), but it is not clear how they lead to cyst formation.
We investigated whether mutations in cyst epithelial cells and corresponding loss of the
PRKCSH gene product (hepatocystin) contributed to cyst development. METHODS: Liver
cyst material was collected through laparoscopic cyst fenestration from 8 patients with PCLD
who had a heterozygous germline mutation in PRKCSH. Tissue sections from 71 cysts (2 …
BACKGROUND & AIMS
Heterozygous germline mutations in PRKCSH cause autosomal dominant polycystic liver disease (PCLD), but it is not clear how they lead to cyst formation. We investigated whether mutations in cyst epithelial cells and corresponding loss of the PRKCSH gene product (hepatocystin) contributed to cyst development.
METHODS
Liver cyst material was collected through laparoscopic cyst fenestration from 8 patients with PCLD who had a heterozygous germline mutation in PRKCSH. Tissue sections from 71 cysts (2–14 per patient) were obtained for hepatocystin staining and mutation analysis. Cyst epithelium was acquired using laser microdissection; DNA was isolated and analyzed for loss of heterozygosity (LOH) and somatic mutations using restriction analysis and sequencing. Common single nucleotide polymorphisms (SNPs) in a 70-kilobase region surrounding the germline mutation were used to determine variations in the genomic region with LOH.
RESULTS
The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71). Hepatocystin was not detected in cyst epithelia with LOH, whereas heterozygous cysts still expressed hepatocystin. The variation observed in the LOH region analysis indicates that cysts develop independently. We also detected somatic mutations in PRKCSH in 17% (2/12) of the cysts without LOH. Trans-heterozygous mutations in SEC63 were not observed.
CONCLUSIONS
Among patients with PCLD who have a heterozygous germline mutation in PRKCSH, we found secondary, somatic mutations (second hits) in more than 76% of the liver cyst epithelia. PCLD is recessive at the cellular level, and loss of functional PRKCSH is an important step in cystogenesis.
Elsevier