title: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
abstract: Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Sorin V
authors.initials: SV
authors.lastname: Fedeles
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Anna-Rachel
authors.initials: AR
authors.lastname: Gallagher
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mitobe
authors.forename: Saori
authors.initials: S
authors.lastname: Nishio
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Cai
authors.forename: Lin
authors.initials: L
authors.lastname: Geng
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003560:Cysts / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005959:Glucosidases / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D005959:Glucosidases; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D050396:TRPP Cation Channels; C484365:Pkhd1 protein, mouse; C512949:Prkcsh protein, mouse