Grant: Operating Grant

Leukodystrophies are a group of degenerative diseases characterized by involvement of the white matter (myelin) of the brain. They are divided into demyelinating (i.e. myelin destruction) and hypomyelinating (i.e. lack of myelin formation) based on their magnetic resonance imaging features. Our group identified recessive mutations in POLR3A and POLR3B as the cause for three different hypomyelinating leukodystrophies. Two other groups identified mutations in these genes in two other leukodystrophies. These new diseases are now known as Pol III-related leukodystrophies. Since these five disorders have only been recently described, there is still much to learn about them. Some patients with a compatible clinical presentation do not have mutation in either gene, suggesting that other gene(s) are mutated. POLR3A and POLR3B encode for two of the 17-subunits of the polymerase III, which is responsible for transcription of DNA into RNA. In particular, Pol III is responsible for the transcription of a very specific subset of small RNAs. Previous experiments suggest that mutations in POLR3A and POLR3B lead to misassembly of Pol III and to a reduced production of specific small RNAs. This research proposal aims at: (1) Completing the clinical, radiological and genetic characterization of these diseases, (2) Studying the impacts of POLR3A and POLR3B mutations on Pol III structure and its major interactors, (3) Characterizing the impact of mutations on Pol III RNA transcription and, (4) Characterizing a Polr3a transgenic mouse. The proposed project will lead to a better understanding of the neurodegenerative Pol III-related leukodystrophies clinically, genetically and pathophysiologically. It will lead to earlier diagnostic, better genetic counselling and medical care for these patients, but also to better understanding of the process of normal myelination, the pathophysiology of hypomyelination which will allow the identification of potential treatments.