Synthetic Lethal Modifier of a New Ciliopathy Gene

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DESCRIPTION (provided by applicant): The ciliopathies comprise a spectrum of disorders unified by defects in primary cilia. Clinical presentations range from primary involvement of a single organ (most often hindbrain, kidney, liver or eye) to more severe presentations, such as Meckel syndrome, with severe and pleiotropic developmental phenotypes in several organs. Several genes have been and continue to be identified for ciliopathy disorders, with the overwhelming majority encoding structural components of primary cilia. Regulatory genes that control cilium-dependent signaling and modifier genes that control the outcome of ciliary defects are only beginning to be tied to pathogenic mechanisms. This project focuses on the synthetic lethal interaction between a transcriptional regulator that control ciliary phenotypes, Zfp423, and an unknown modifier gene. Zfp423 encodes a 30-zinc finger transcription factor required in several signal transduction pathways and in multiple organ systems. Animals that lack Zfp423 have prominent brain malformations with a high frequency of hydrocephalus as well as defects in several peripheral tissues. The distribution of phenotypes in surviving animals is dependent on both modifier genes and apparently stochastic processes. However, on the most commonly used strain background, no mutant animals survive. Genetic mapping identifies a single major locus linked to embryonic and perinatal lethality. The aims of this proposal will identify this synthetic lethal modifier locus, elucidate its mechanism and place it in the context of other genes in the ciliopathy network.