Polycystic liver diseases (PCLDs) are a heterogeneous group of genetic disorders characterized by the development of multiple fluid-filled cysts in the liver, which derive from cholangiocytes, the epithelial cells lining the bile ducts. When these cysts grow, symptoms such as abdominal distension, nausea, and abdominal pain may occur. PCLDs may exist isolated (i.e., autosomal dominant polycystic liver disease, ADPLD) or in combination with renal cystogenesis (i.e., autosomal dominant polycystic kidney disease and autosomal recessive polycystic liver disease). The exact prevalence of PCLDs is unknown, but is estimated to occur in approximately 1:1000 persons. Although the pathogenesis of each form of PCLD appears to be different, increasing evidences indicate that hepatic cystogenesis is a phenomenon that may involve somatic loss of heterozygosity (LOH) in those pathological conditions inherited in a dominant form. A recent report, using highly sophisticated methodology, demonstrated that ADPLD patients with a germline mutation in the protein kinase C substrate 80K-H (PRKCSH) gene mostly develop hepatic cystogenesis through a second somatic mutation. While hepatocystin, the PRKCSH-encoding protein, was absent in the hepatic cysts with LOH, it was still expressed in the heterozygous cysts. On the other hand, no additional trans-heterozygous mutations on the SEC63 homolog (S. cerevisiae/SEC63) gene (also involved in the development of PCLDs) were observed. These data indicate that PCLD is recessive at the cellular level, and point out the important role of hepatocystin loss in cystogenesis. In this commentary, we discuss the knowledge regarding the role of somatic second-hit mutations in the development of PCLDs, and the most relevant findings have been highlighted.
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