title: Cysts of PRKCSH mutated polycystic liver disease patients lack hepatocystin but express Sec63p.
abstract: Polycystic liver disease (PCLD) is an inherited disorder caused by mutations in either PRKCSH (hepatocystin) or SEC63 (Sec63p). However, expression patterns of the implicated proteins in diseased and normal liver are unknown. We analyzed subcellular and cellular localization of hepatocystin and Sec63p using cell fractionation, immunofluorescence, and immunohistochemical methods. Expression patterns were assessed in fetal liver, PCLD liver, and normal adult liver. We found hepatocystin and Sec63p expression predominantly in the endoplasmic reticulum. In fetal tissue, there was intense expression of hepatocystin in ductal plate, bile ducts, and hepatocytes. However, Sec63p staining was prominent in early hepatocytes only and weak in bile ducts throughout development. In PCLD tissue, hepatocystin was expressed in hepatocytes, bile ducts, and in cyst epithelium of patients negative for PRKCSH mutation. In contrast, the majority of cysts from PRKCSH mutation carriers did not express hepatocystin. Sec63p expression was observed in all cyst epithelia regardless of mutational state. We conclude that hepatocystin is probably required for development of bile ducts and does not interact with Sec63p. The results support the hypothesis that cyst formation in PCLD results from a cellular recessive mechanism involving loss of hepatocystin. Cystogenesis in SEC63-associated PCLD occurs via a different mechanism.
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. e.waanders@mdl.umcn.nl
authors.forename: Esmé
authors.initials: E
authors.lastname: Waanders
authors.forename: Huib J E
authors.initials: HJ
authors.lastname: Croes
authors.forename: Cathy N
authors.initials: CN
authors.lastname: Maass
authors.forename: René H M
authors.initials: RH
authors.lastname: te Morsche
authors.forename: Hendrikus J A A
authors.initials: HJ
authors.lastname: van Geffen
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Jack A M
authors.initials: JA
authors.lastname: Fransen
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
mesh_terms: D000328:Adult; D000368:Aged; D001652:Bile Ducts / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002458:Cell Fractionation; D003560:Cysts / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005704:Gallbladder / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D005959:Glucosidases / Q000235:genetics*; D006367:HeLa Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018613:Microscopy, Confocal; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D016601:RNA-Binding Proteins; D055815:Young Adult
chemical_list: 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