Congenital disorders of glycosylation in hepatology: the example of polycystic liver disease.
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.
Department of Gastroenterology and Hepatology, Institute for Genetic & Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Manoe J
MJ
Janssen
Esmé
E
Waanders
Jannes
J
Woudenberg
Dirk J
DJ
Lefeber
Joost P H
JP
Drenth
D002135:Calcium-Binding Proteins; D003560:Cysts / Q000151:congenital* / Q000378:metabolism; D005959:Glucosidases / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008107:Liver Diseases / Q000151:congenital* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones; D016601:RNA-Binding Proteins
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D016601:RNA-Binding Proteins; C487464:SEC63 protein, human; D005959:Glucosidases; C070368:PRKCSH protein, human