A Pkd1-Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease.

Liu D, Wang CJ, Judge DP, Halushka MK, Ni J, Habashi JP, Moslehi J, Bedja D, Gabrielson KL, Xu H, Qian F, Huso D, Dietz HC, Germino GG, Watnick T
J Am Soc Nephrol. 2014 25 (1): 81-91

PMID: 24071006 · PMCID: PMC3871766 · DOI:10.1681/ASN.2012050486

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.

MeSH Terms (24)

Animals Disease Models, Animal Epistasis, Genetic Female Fibrillin-1 Fibrillins Genetic Association Studies Haploinsufficiency Heterozygote Humans Male Marfan Syndrome Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Microfilament Proteins Mutation Polycystic Kidney, Autosomal Dominant Signal Transduction Transforming Growth Factor beta TRPP Cation Channels Vascular Diseases

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