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Genetics of polycystic liver diseases

Lee-Law, Pui Y.a,b; van de Laarschot, Liyanne F.M.b; Banales, Jesus M.a,c; Drenth, Joost P.H.b

Current Opinion in Gastroenterology: March 2019 - Volume 35 - Issue 2 - p 65–72
doi: 10.1097/MOG.0000000000000514
BILIARY TRACT: Edited by Chantal Housset

Purpose of review This review provides an outline of the most recent insights and significant discoveries regarding the genetic mechanisms involved in polycystic liver disease.

Recent findings Polycystic liver disease includes a heterogeneous group of genetic disorders characterized by multiple hepatic cysts. Isolated liver cysts are caused by mutations in Protein Kinase C Substrate 80K-H (PRKCSH), SEC63, and LDL Receptor Related Protein 5 (LRP5), whereas Polycystic Kidney Disease (PKD)1, PKD2, and PKHD1 mutations cause kidney cysts often accompanied by liver cysts. Glucosidase II Alpha Subunit (GANAB) has been reported to cause both phenotypes. These mutations, together with the newly identified ones in SEC61B and Alpha-1,3-Glucosyltransferase (ALG8), can be found in ∼50% of patients with isolated polycystic liver disease. Somatic second hit-mutations are hypothesized as driving force leading to cystogenesis. Subsequently, loss of heterozygosity in the cystic tissue aggravates disease progression. All genetic mutations lead to reduced levels of functional polycystin-1. This ciliary protein is therefore considered to be the central factor in the development and severity of liver cysts.

Summary Recent advances of the genetic complexity leading to hepatic cystogenesis provide novel candidate genes and important mechanistic insights with polycystin-1 as a common denominator.

aDepartment of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain

bDepartment of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands

cIkerbasque, Basque Foundation for Science, Bilbao, Spain

Correspondence to Joost P.H. Drenth, MD, PhD, Department of Gastroenterology and Hepatology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 243616999; fax: +31 24 363 5129; e-mail:

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