Congenital disorders of glycosylation in hepatology: The example of polycystic liver disease

Abstract

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.

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

“…9 Because it is possible that AQP11 localizes to ER, we hypothesized that mechanisms of cystogenesis in the kidney of the AQP11(2/2) mouse were related to impaired quality control and aberrant trafficking of PC-1 and PC-2. PC-1 is a multidomain glycoprotein that is cleaved at a G protein-coupled receptor proteolytic site and divided into an N-terminal product (NTP) and a C-terminal product.…”

Medical and surgical treatment options for polycystic liver disease1

“…11,12 The protein products of these genes (hepatocystin and Sec63, respectively) act in concert to achieve proper topology and folding of integral membrane or secreted glycoproteins in the endoplasmic reticulum (ER). 13 Liver cysts are thought to arise from malformation of the ductal plate during embryonic liver development. Normal bile ducts arise from the ductal plate through growth and apoptosis.…”

Current management of noninfectious hepatic cystic lesions: A review of the literature

“…Both have an autosomal dominant transmission and similar clinical presentation. PCLD associated with ADPKD is linked with mutations in the PKD1 (short arm of chromosome 16, encoding polycystin-1) or PKD2 gene (chromosome 4, encoding polycystin-2), whereas isolated PCLD is associated with heterozygous mutation in PRKC-SH or SEC63 genes [21][22][23][24][25][26] . Overall prevalence is the same in gender, but female population is associated with more severe liver disease [27] .…”