A Genetic Interaction Network of Five Genes for Human Polycystic Kidney and Liver Diseases Defines Polycystin-1 As the Central Determinant of Cyst Formation

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Jun 21

PMID 21685914

Citations 132

Authors

Sorin V Fedeles

Xin Tian

Anna-Rachel Gallagher

Michihiro Mitobe

Saori Nishio

Seung Hun Lee

Yiqiang Cai

Lin Geng

Craig M Crews

Stefan Somlo

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Wu G, Tian X, Nishimura S, Markowitz G, DAgati V, Park J . Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum Mol Genet. 2002; 11(16):1845-54. DOI: 10.1093/hmg/11.16.1845. View

Garcia-Gonzalez M, Menezes L, Piontek K, Kaimori J, Huso D, Watnick T . Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum Mol Genet. 2007; 16(16):1940-50. PMC: 2085232. DOI: 10.1093/hmg/ddm141. View

Lalioti M, Heath J . A new method for generating point mutations in bacterial artificial chromosomes by homologous recombination in Escherichia coli. Nucleic Acids Res. 2001; 29(3):E14. PMC: 30415. DOI: 10.1093/nar/29.3.e14. View

Pazour G, San Agustin J, Follit J, Rosenbaum J, Witman G . Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol. 2002; 12(11):R378-80. DOI: 10.1016/s0960-9822(02)00877-1. View

Hanaoka K, Qian F, Boletta A, Bhunia A, Piontek K, Tsiokas L . Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature. 2001; 408(6815):990-4. DOI: 10.1038/35050128. View

Jiang S, Chiou Y, Wang E, Lin H, Lin Y, Chi Y . Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol. 2006; 168(1):205-20. PMC: 1592650. DOI: 10.2353/ajpath.2006.050342. View

. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell. 1994; 77(6):881-94. DOI: 10.1016/0092-8674(94)90137-6. View

Nauli S, Alenghat F, Luo Y, Williams E, Vassilev P, Li X . Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003; 33(2):129-37. DOI: 10.1038/ng1076. View

Qian F, Watnick T, Onuchic L, Germino G . The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996; 87(6):979-87. DOI: 10.1016/s0092-8674(00)81793-6. View

10.

Lyman S, Schekman R . Binding of secretory precursor polypeptides to a translocon subcomplex is regulated by BiP. Cell. 1997; 88(1):85-96. DOI: 10.1016/s0092-8674(00)81861-9. View

11.

Drenth J, Te Morsche R, Smink R, Bonifacino J, Jansen J . Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat Genet. 2003; 33(3):345-7. DOI: 10.1038/ng1104. View

12.

Piontek K, Menezes L, Garcia-Gonzalez M, Huso D, Germino G . A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med. 2007; 13(12):1490-5. PMC: 2302790. DOI: 10.1038/nm1675. View

13.

Trombetta E, Simons J, Helenius A . Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit. J Biol Chem. 1996; 271(44):27509-16. DOI: 10.1074/jbc.271.44.27509. View

14.

Stigliano I, Caramelo J, Labriola C, Parodi A, DAlessio C . Glucosidase II beta subunit modulates N-glycan trimming in fission yeasts and mammals. Mol Biol Cell. 2009; 20(17):3974-84. PMC: 2735495. DOI: 10.1091/mbc.e09-04-0316. View

15.

Rossetti S, Kubly V, Consugar M, Hopp K, Roy S, Horsley S . Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 2009; 75(8):848-55. PMC: 2813773. DOI: 10.1038/ki.2008.686. View

16.

Reynolds D, Falk C, Li A, King B, Kamath P, Huston 3rd J . Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am J Hum Genet. 2000; 67(6):1598-604. PMC: 1287938. DOI: 10.1086/316904. View

17.

Wu G, Markowitz G, Li L, DAgati V, Factor S, Geng L . Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet. 1999; 24(1):75-8. DOI: 10.1038/71724. View

18.

Qian Q, Li A, King B, Kamath P, Lager D, Huston 3rd J . Clinical profile of autosomal dominant polycystic liver disease. Hepatology. 2002; 37(1):164-71. DOI: 10.1053/jhep.2003.50006. View

19.

Young B, Craven R, Reid P, Willer M, Stirling C . Sec63p and Kar2p are required for the translocation of SRP-dependent precursors into the yeast endoplasmic reticulum in vivo. EMBO J. 2001; 20(1-2):262-71. PMC: 140194. DOI: 10.1093/emboj/20.1.262. View

20.

Li A, Davila S, Furu L, Qian Q, Tian X, Kamath P . Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am J Hum Genet. 2003; 72(3):691-703. PMC: 1180260. DOI: 10.1086/368295. View