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PMID:21685914

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Citation

Fedeles, SV, Tian, X, Gallagher, AR, Mitobe, M, Nishio, S, Lee, SH, Cai, Y, Geng, L, Crews, CM and Somlo, S (2011) A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43:639-47

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.

Links

PubMed PMC3547075 Online version:10.1038/ng.860

Keywords

Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cysts/genetics; Cysts/metabolism; Cysts/pathology; Female; Glucosidases/genetics; Glucosidases/metabolism; Immunoenzyme Techniques; Immunoprecipitation; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Liver Diseases/genetics; Liver Diseases/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Polycystic Kidney Diseases/genetics; Polycystic Kidney Diseases/metabolism; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; TRPP Cation Channels/genetics; TRPP Cation Channels/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GLU2B

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2155302

P

Seeded From UniProt

complete

MOUSE:GLU2B

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5442302

P

Seeded From UniProt

complete

MOUSE:GLU2B

acts_upstream_of_or_within

GO:0006807: nitrogen compound metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97603

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1099818

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0001822: kidney development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1099818

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0006807: nitrogen compound metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:107877
MGI:MGI:2155302

P

Seeded From UniProt

complete

MOUSE:PKD2

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97603

P

Seeded From UniProt

complete

MOUSE:PKD2

acts_upstream_of_or_within

GO:0001822: kidney development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97603

P

Seeded From UniProt

complete

MOUSE:PKD2

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SEC63

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5442171

P

Seeded From UniProt

complete

MOUSE:SEC63

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:107877

P

Seeded From UniProt

complete

MOUSE:SEC63

acts_upstream_of_or_within

GO:0006807: nitrogen compound metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97603

P

Seeded From UniProt

complete

MOUSE:SEC63

acts_upstream_of_or_within

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5442171

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0001822: kidney development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O35245

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O35245

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0006807: nitrogen compound metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O08795
UniProtKB:Q8VHE0

P

Seeded From UniProt

complete

MOUSE:PKD1

acts_upstream_of_or_within

GO:0060236: regulation of mitotic spindle organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3793793

P

Seeded From UniProt

complete

MOUSE:PKD2

acts_upstream_of_or_within

GO:0001822: kidney development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O08852

P

Seeded From UniProt

complete

MOUSE:PKD2

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O08852

P

Seeded From UniProt

complete

MOUSE:PKD2

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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