Project Summary Pol III-associated leukodystrophy is an autosomal recessive neurodegenerative disease linked to mutations in subunits of RNA polymerase III (Pol III). The clinical and radiologic spectrum of the disorder has only recently been defined. Pol III-associated leukodystrophy is characterized by hypomyelination of cerebral white matter and presents as a progressive decline in motor function, developmental delay and intellectual disability. Disease onset typically occurs during childhood but the age range at diagnosis is broad, reflecting the variable severity and slow progression of the disease. Other clinical characteristics include myopia, hypodontia and endocrine abnormalities but these features are not always present. The mechanism of pathogenesis is unknown and no therapeutic options are available. Further progress in understanding this disease is limited by the lack of model systems. Thus, the goal of this research is to develop a mouse model of Pol III-associated leukodystrophy. We have created a knock-in mouse expressing clinically-defined Pol III-associated leukodystrophy mutations. We will characterize the behavioral, radiologic and neuropathologic phenotypes of these mice. Phenotypic changes will be correlated with the impact of the mutation on Pol III transcription, tRNA biogenesis and protein synthesis. In addition, we will test a model for genetic suppression of Pol III-associated leukodystrophy phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-associated leukodystrophy and will provide a model system for testing therapeutic approaches targeting the disease.
|Effective start/end date||3/1/19 → 2/28/21|
- Eunice Kennedy Shriver National Institute of Child Health and Human Development: $250,500.00
- Clinical Neurology