Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated with upregulation of the mTOR pathway

Alessandro Zullo, Daniela Iaconis, Adriano Barra, Alessandra Cantone, Nadia Messaddeq, Giovanbattista Capasso, Pascal Dollé, Peter Igarashi, Brunella Franco

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


The oral-facial-digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited renal cystic disease. It is transmitted as an X-linked dominant, male lethal disorder and is caused by mutations in the OFD1 gene. Previous studies demonstrated that OFDI belongs to the growing number of disorders ascribed to dysfunction of primary cilia. We generated a conditional inactivation of the mouse Ofd1 gene using the Ksp-Cre transgenic line, which resulted in a viable model characterized by renal cystic disease and progressive impairment of renal function. The study of this model allowed us to demonstrate that primary cilia initially form and then disappear after the development of cysts, suggesting that the absence of primary cilia is a consequence rather than the primary cause of renal cystic disease. Immunofluorescence and western blotting analysis revealed upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of renal cysts and a decrease in the cystic index compared with untreated mutant animals, suggesting that dysregulation of this pathway in our model is mTOR-dependent. The animal model we have generated could thus represent a valuable tool to understand the molecular link between mTOR and cyst development, and eventually to the identification of novel drug targets for renal cystic disease.

Original languageEnglish (US)
Article numberddq180
Pages (from-to)2792-2803
Number of pages12
JournalHuman molecular genetics
Issue number14
StatePublished - May 5 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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