The long tail of a STAR: a matter of cell differentiation impairment and aberrant cytoskeletal dynamics to explain STAR syndrome phenotype

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

STAR syndrome is a rare X-linked dominant developmental disorder with male lethality and severe clinical phenotype in female. STAR syndrome is caused by mutations of the FAM58A gene. This gene encodes for Cyclin M, a poorly known protein that regulates both Actin polymerization and the formation of a particular cellular structure, called “cilium”, which regulates a wide range of cellular activities. STAR syndrome is characterized from different clinical features, including toe Syndactyly, Telecanthus, Anogenital and Renal malformations, that give rise to the acronym. Even if it was recently classified as a ciliopathy, the molecular causes of its severe phenotype are still obscure and, currently, there is no cure for STAR syndrome. Our hypothesis is that, when Cyclin M does not function (as in the case of STAR syndrome), there is an imbalance in cilia/Actin dynamics that could impact both cell differentiation and cytoskeletal structure of certain differentiated cell types. This overall impairment would explain the drastic loss of renal functionality shown by STAR patients and also underlie defects in neurogenesis. Our main objectives will be to understand how, when Cyclin M does not function, cilia/Actin dynamics are hampered and how this overall impairment might impact stem cell maintenance and differentiation. Successful conclusion of these studies will improve our knowledge of the mechanisms at the basis of STAR syndrome and, hopefully, lay the groundwork for development of new therapeutic approaches.