Exploring the role of RSPRY1 in osteogenesis to unravel the pathogenic mechanisms of Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

Spondyloepimetaphyseal Dysplasias are a heterogeneous group of rare genetic diseases characterized by defects in bone development resulting in short stature and other skeletal abnormalities. One subtype of these diseases is also presenting with developmental delay and intellectual disability. This more severe type is caused by mutations in the RSPRY1 gene, but nothing is known yet about its function. By looking at the predicted structure of RSPRY1 we observed a similarity with proteins that function to regulate other cellular components, and hypothesized that alterations of this activity may be at the basis of the disease. To test our hypothesis, we will produce the protein, either in its normal or mutated form, and test its activity in vitro to highlight potential defects caused by the mutations. As proteins often work together to achieve their function, we will also analyse which proteins RSPRY1 can associate with, and how its mutations change this interaction network. We will also use a cellular model that we will modify to express the mutated form of RSPRY1. We will next induce these cells to differentiate into bone-like cells and see if the presence of mutated forms of RSPRY1 may interfere with ability to become bone cells, as we would expect. At the end of this project we expect to have gained substantial knowledge about RSPRY1 function inside the cell and in the bone formation process. These results will lay the basis for future studies going deeper into these processes to ultimately define the precise mechanism of action of RSPRY1 and how its alteration results in bone defects. This information will be important for the development of future therapies.