Impact of the WFS1-related mutations on immune system dysregulation in Wolfram Syndrome 1

Wolfram syndrome (WFS1) is a rare genetic disorder associated to a broad range of clinical manifestations among patients. The disease is caused by mutations in the WFS1 gene, encoding for the Wolframin protein, localized in the majority of human tissues, where it plays important roles in several cellular functions. More than 200 WFS1 variants are known to generate altered proteins in their structure and function. Wolframin alterations dysregulate different cellular processes leading, for example, to an inflammatory condition at both systemic and tissue level and immune cell imbalance. Although Wolframin is also expressed by immune cells, its role in inflammation and immune responses has not been deeply explored. Therefore, our project proposes to increase the knowledge about the immune system of WFS1 by investigating the inflammatory status and alterations of gene and protein expression in immune cellular components. These findings will guide into the associations between specific immune characteristic and patient-related mutation. As WFS1 is an heterogenous disease we foresee to detect different immunological profiles; therefore, we will categorize the patients according to common features to further characterize the molecular mechanisms causing the observed alterations. Moreover, we will set up a mouse model of WFS1 in which we will reconstitute the immune system of patients in order to validate in vivo the immune dysregulations we detected. This model will allow us to study in a more reliable way what happens in the patient. These investigations will highlight new potential target candidates for future personalizedbased therapeutic approaches