Dissecting the molecular and cellular mechanisms of the MACS/RIN2 syndrome

The MACS/RIN2 syndrome is a rare, genetically inherited, and progressive disorder that has been diagnosed up to now in 9 patients living in Turkey, Middle East and North Africa areas. This severe disease is characterized by invalidating malformations of skin, joints, and skeleton that appears to be due to an abnormal deposition of a crucial structural element of our body known as extracellular matrix (ECM). Accordingly, we recently discovered that RIN2, the mutated gene responsible for this syndrome, is an extremely important regulator of the mechanisms by which cells produce and physically attach to the ECM. We will work to elucidate the molecular mechanisms of RIN2 functioning, something that at present is poorly understood. To this aim, we will investigate how two novel molecules that we found to physically interact with RIN2 could team up with it to control the production of and the attachment of cells to the ECM. The identified molecules and mechanisms will represent pharmacological targets for the development of therapies aimed at slowing down or even stopping the evolution of this progressively worsening disease. In strict collaboration with Italian and German researchers, we will also develop genetically modified mice lacking Rin2, with the aim of generating the first animal model of the human MACS/RIN2 syndrome. Such an animal model will prove useful for additional future studies on the pathological mechanisms responsible for this severe disease in humans.