Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain.
Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Curr Opin Gastroenterol. 2019 Mar;35(2):65-72. doi: 10.1097/MOG.0000000000000514.
This review provides an outline of the most recent insights and significant discoveries regarding the genetic mechanisms involved in polycystic liver disease.
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.
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.
本文概述了与多囊肝疾病相关的遗传机制的最新见解和重要发现。
多囊肝疾病包括一组遗传异质性疾病，其特征为多发性肝囊肿。孤立性肝囊肿是由蛋白激酶 C 底物 80K-H（PRKCSH）、SEC63 和 LDL 受体相关蛋白 5（LRP5）的突变引起的，而多囊肾病（PKD）1、PKD2 和 PKHD1 的突变则导致肾脏囊肿，常伴有肝脏囊肿。葡萄糖苷酶 II Alpha 亚基（GANAB）已被报道可引起这两种表型。这些突变，以及在 SEC61B 和 Alpha-1,3-葡糖苷基转移酶（ALG8）中发现的新突变，可在约 50%的孤立性多囊肝疾病患者中发现。体细胞二次打击突变被假设为导致囊肿发生的驱动力。随后，囊性组织中的杂合性丢失加剧了疾病的进展。所有的遗传突变导致功能性多囊蛋白-1的水平降低。因此，这种纤毛蛋白被认为是肝囊肿发生和严重程度的核心因素。
导致肝囊肿发生的遗传复杂性的最新进展提供了新的候选基因和重要的机制见解，多囊蛋白-1 是一个共同的因素。
