New mouse model for polycystic kidney disease with both recessive and dominant gene effects

Abstract

In the course of studying the genetics of chlorambucil mutagenesis, we have uncovered a new model for autosomal polycystic kidney disease (PKD). In the homozygous condition, the gene, jcpk, causes a very severe disease characterized by cysts in all segments of the nephron. Death usually occurs before 10 days of age. Extrarenal involvement was also noted; enlarged bile ducts, pancreatic ducts, and gall bladder often accompanied the PKD. In addition, approximately 25% of the aged +/jcpk heterozygotes show evidence of glomerulocystic disease. This gene maps to Chromosome 10 between two DNA markers, D10Mit20 and D10Mit42. Because this gene causes extrarenal abnormalities and because it has a heterozygote effect, it may be an informative animal model for the commonly occurring human adult dominant PKD.

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

“…Glomerular cysts are found in juvenile patients with autosomal dominant PKD (16) and have also been reported for tuberous sclerosis complex (17,18), juvenile NPH (19), OFD1 (20), and hypoplastic familial GCKD linked to mutations in HNF1␤ (21). Glomerular cysts are also present in the jcpk (juvenile congenital polycystic kidney) mouse (22), a model for autosomal recessive PKD due to a mutation in the Bicc1 gene (24). In addition, we analyzed expression of Pkhd1, Tg737, and Kif3a, which are associated with forms of PKD that do not present obvious glomerular cysts but have been linked to the ciliary apparatus (14,(24)(25)(26), as well as Dctn5 and two components of motile cilia, Ird and D2lic.…”

“…1), marginally but consistently repressed in Wwtr1 KO kidneys, localize to cilia. Bicc1 is mutated in the jcpk mouse, and Ϸ25% of aged heterozygotes present with cysts of glomerular origin (22). Wwtr1 Ϫ/Ϫ mice did not reveal some of the other defects linked to mutations in Tsc1 or Ofd1, possibly reflecting their only partial down-regulation or Wwtr1-independent regulation in other tissues.…”

“…Mutations in HNF1␤ have been implicated in GCKD (22). Conditional renal inactivation of Hnf1␤ in mice leads to cysts predominantly derived from CD and to lesser extent glomerula, and cyst formation was correlated with a partial down-regulation of Umod, Pkhd1, Pkd2, Nphp1, and Tg737 (30).…”

Characterization of a Novel Polycystic Kidney Rat Model with Accompanying Polycystic Liver.

“…The adult type is an autosomal dominant polycystic kidney disease (ADPKD) and the infant type is an autosomal recessive polycystic kidney disease (ARPKD). Although many spontaneously occurring polycystic kidney mouse models have been established [1,3,4,8,10,12,13], the Cy rat [2,5,6,11] and the chin rat [9] are the only rat models. At Charles River Japan Inc., we have identified a female rat with polycysts on both the kidney and liver derived from an ongoing colony of Crj:CD (SD) rats.…”

Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2)

“…46 Several mouse models with polycystic kidneys do not have defects linked to the syntenic regions of the new loci. [47][48][49][50][51][52][53] Our search leaves us with the interesting result that there are three novel genes, the products of which show significant homology to polycystin-1 and 2. Two of them, the PKD2L and PKD2L2 gene products, have a remarkably high homology to each other and polycystin-2.…”