Centriolar distal appendage: one nanoscopic structure, many diseases

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Ciliopathies are a large group of genetic disorders sharing the common feature to present malfunction of a structure present in nearly every cell of our body: the cilium. While the list of genes affected by ciliopathy causing mutations is still growing, phenotypes in the patients show recurrent elements: retinal degeneration and kidney failure are among them. Even patients carrying mutations affecting the same ciliary gene can display very diverse clinical manifestations: in some, the affected organ will be solely the kidney, in others the sole retina and in still others both. The molecular mechanisms by which mutations of individual components of the cilium cause one or the other disease are largely obscure. In this project, we plan to study rare mutations affecting the CEP83 gene causing infantile nephronophthisis, a form of kidney failure occurring in kids at the age of 3 or earlier. Strikingly, however, in other kids CEP83 mutations cause retinal degeneration without impacting the kidney. Concretely, we will use advanced microscopy methods to define the structural alterations of the cilium caused by CEP83 mutations in kidney as well as in retinal cells. Moreover, by analysing the ciliary protein composition both in retinal as well as in kidney cells carrying the same CEP83 mutation, we will address how the heterogeneity in the clinical manifestation arises. Finally, we will exploit a method known as CRISPR to identify other cellular components interacting with the CEP83 mutant cilium. This last effort will allow to define metabolic pathways concurring to the occurrence of the diseased phenotype. This will in turn identify new targets amenable to pharmacologic intervention, thereby providing a conceptual basis for novel clinical treatment regimens for ciliopathies.