Cystic kidney disease and related ciliopathies are caused by pathogenic variants in genes that commonly result in ciliary dysfunction. For a substantial number of individuals affected by those cilia-r Show more
Cystic kidney disease and related ciliopathies are caused by pathogenic variants in genes that commonly result in ciliary dysfunction. For a substantial number of individuals affected by those cilia-related diseases, the causative gene remains unknown. Using massively parallel sequencing, we here identified a pathogenic bi-allelic variant in the gene encoding PALS1-associated tight junction protein ([PATJ] also known as inactivation-no-afterpotential D-like, INADL) in an individual with ciliopathy. The affected fetus carried the homozygous truncating PATJ nonsense variant c.830delC (p.Pro277fsX), and presented with a syndromic phenotype mainly characterized by polycystic kidney disease and hydrocephalus. Using zebrafish (Danio rerio) as a vertebrate in vivo model organism, we could validate our patient findings and demonstrated a ciliopathy phenotype. In addition, we were able to address a hitherto not described role of Patj for cilia formation and function. Taken together, with the Crumbs cell polarity complex member PATJ, we add a new member to the large family of ciliopathy-related human disease proteins that is different from the classical ciliopathy protein classes, and may offer new perspectives for drug development. Show less
The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular Show more
The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ's function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7. Show less