Grant: Operating Grant

Leukodystrophies are a group of degenerative diseases characterized by involvement of the white matter of the brain. They are divided into hypomyelinating (i.e. lack of myelin formation) and non-hypomyelinating (i.e. abnormal myelin maintenance) based on their magnetic resonance imaging features. Our group identified mutations in POLR3A and POLR3B as the cause for 4H or POLR3 (hypomyelinating) leukodystrophy. POLR3A and POLR3B encode for two of the 17-subunits of the RNA polymerase III (POLR3), which is responsible for transcription of DNA into RNA of a subset of specific small RNAs important for survival of the cell. Our group recently discovered more than 60 mutations or mistakes in POLR3A and POLR3B, as well as three novel genes causing this disorder, and have found that some mistakes in three of these genes, lead to defects in assembly, localisation or function of POLR3, making it more difficult for this important complex to do its work properly. We have hypothesized that this would lead to abnormal levels certain key RNAs important for the development of myelin (white matter) of the brain. In this project, we want to explore in greater details the pathophysiology of the disease, study it's clinical and imaging characteristics and their evolution with time in order to develop an eventual treatment trial. The proposed project will lead to a better understanding of the disorder at all levels, leading to earlier diagnostic, better genetic counselling and medical care for the patients and their families, but also to better understanding of the pathophysiology of the disease, and the process of normal myelination, which will allow the identification of potential treatments for POLR3-HLD and hopefully for a greater number of disorders affecting the white matter of the brain.