MOLECULAR BASIS OF CHARCOT MARIE TOOTH TYPE 2B DISEASE

The hereditary sensory neuropathies (HSNs) are a heterogeneous group of disorders characterized by prominent sensory loss, often accompanied by the development of skin ulcers, arthropathy, osteomyelitis and amputations. Similar features are seen in Charcot-Marie-Tooth disease type 2B to the extent that some scientist have argued that this disease would be better classified as a form of HSN. The age of onset of this kind of disease is around 20 years. Tipically sensory nerves are badly affected and therefore there is a high incidence of ulcero mutilating complications. Recently it has been discovered that the autosomal dominant axonal Charcot-Marie-Tooth type 2B neuropathy is caused by mutations in the gene coding for the Rab7 protein. These data strongly suggest that the Rab7 protein plays a fundamental role in the development of this kind of diseases but at the moment it is not clear how. In this project we propose to study, at the molecular level, the function of the Rab7 protein and of its interacting proteins in the peripheral nervous system. In particular, we propose to study the effect caused by the mutated Rab7 proteins in neuronal cells to be able to start to clarify the molecular mechanism underlying the sensory neuronal degeneration characteristic of this disease, where these mutated proteins are present and expressed. The identification of the molecular mechanisms responsible for this ulcero mutilating neuropathy might open the possibility in the future to design specific and effective therapeutic tools.