Department of Gastroenterology and Hepatology, Institute for Genetic & Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
J Hepatol. 2010 Mar;52(3):432-40. doi: 10.1016/j.jhep.2009.12.011. Epub 2009 Dec 24.
Autosomal dominant polycystic liver disease (PCLD) is a rare progressive disorder characterized by an increased liver volume due to many (>20) fluid-filled cysts of biliary origin. Disease causing mutations in PRKCSH or SEC63 are found in approximately 25% of the PCLD patients. Both gene products function in the endoplasmic reticulum, however, the molecular mechanism behind cyst formation remains to be elucidated. As part of the translocon complex, SEC63 plays a role in protein import into the ER and is implicated in the export of unfolded proteins to the cytoplasm during ER-associated degradation (ERAD). PRKCSH codes for the beta-subunit of glucosidase II (hepatocystin), which cleaves two glucose residues of Glc(3)Man(9)GlcNAc(2) N-glycans on proteins. Hepatocystin is thereby directly involved in the protein folding process by regulating protein binding to calnexin/calreticulin in the ER. A separate group of genetic diseases affecting protein N-glycosylation in the ER is formed by the congenital disorders of glycosylation (CDG). In distinct subtypes of this autosomal recessive multisystem disease specific liver symptoms have been reported that overlap with PCLD. Recent research revealed novel insights in PCLD disease pathology such as the absence of hepatocystin from cyst epithelia indicating a two-hit model for PCLD cystogenesis. This opens the way to speculate about a recessive mechanism for PCLD pathophysiology and shared molecular pathways between CDG and PCLD. In this review we will discuss the clinical-genetic features of PCLD and CDG as well as their biochemical pathways with the aim to identify novel directions of research into cystogenesis.
常染色体显性遗传性多囊肝病（PCLD）是一种罕见的进行性疾病，其特征是由于许多（>20）起源于胆管的充满液体的囊肿导致肝脏体积增加。在大约 25%的 PCLD 患者中发现了 PRKCSH 或 SEC63 的致病突变。这两种基因产物都在内质网中发挥作用，然而，囊肿形成的分子机制仍有待阐明。作为易位子复合物的一部分，SEC63 在蛋白质向内质网的输入中起作用，并在 ER 相关降解（ERAD）期间参与未折叠蛋白质向细胞质的输出。PRKCSH 编码葡萄糖苷酶 II（肝囊素）的β亚基，该酶在蛋白质上切割 Glc(3)Man(9)GlcNAc(2)N-聚糖的两个葡萄糖残基。肝囊素通过调节内质网中蛋白质与钙连蛋白/钙网蛋白的结合，直接参与蛋白质折叠过程。一组影响内质网中蛋白质 N-糖基化的遗传疾病由先天性糖基化障碍（CDG）形成。在这种常染色体隐性多系统疾病的不同亚型中，已经报道了特定的肝脏症状与 PCLD 重叠。最近的研究揭示了 PCLD 疾病病理学的新见解，例如囊肿上皮中缺乏肝囊素，这表明 PCLD 囊肿发生存在双打击模型。这为推测 PCLD 病理生理学的隐性机制以及 CDG 和 PCLD 之间的共享分子途径开辟了道路。在这篇综述中，我们将讨论 PCLD 和 CDG 的临床遗传特征及其生化途径，目的是确定对囊肿发生的新的研究方向。
