Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease

Hum Mol Genet. 2002 Aug 1;11(16):1845-54. doi: 10.1093/hmg/11.16.1845.


Autosomal dominant polycystic kidney disease (ADPKD) occurs by germline mutation in PKD1 or PKD2. Evidence of homozygous inactivation of either gene in human cyst lining cells as well as in mouse knockout models strongly supports a two-hit mechanism for cyst formation. Discovery of trans-heterozygous mutations in PKD1 and PKD2 in a minority of human renal cysts has led to the proposal that such mutations also can play a role in cyst formation. In the current study, we investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1(+/-), Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the two-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 (+/-) mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1(+/-) : Pkd2 (+/-) mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. The data suggest a modifier role for the 'trans' polycystin gene in cystic kidney disease, and support a contribution from threshold effects to cyst formation and growth.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Heterozygote
  • Humans
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Mutation*
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Proteins / genetics*
  • Proteins / metabolism
  • TRPP Cation Channels


  • Membrane Proteins
  • Proteins
  • TRPP Cation Channels
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein