Validating POLR1A p.C1562F as the Cause of a Novel Infantile Encephalopathy with Infantile Spasms
Principle Investigator: K. Nicole Weaver, MD
Ribosomes are the cellular machinery responsible for making proteins. When production of ribosomes is disrupted, a variety of birth defects and other health problems can occur. The gene POLR1A is required for making ribosomes. Our team has previously demonstrated that pathogenic variants in POLR1A can cause congenital craniofacial and limb differences in humans. We are currently working with a mouse model to understand the underlying mechanism.
In conjunction with international clinical collaborators, we recently identified two unrelated children with the same suspected pathogenic variant in POLR1A (p.C1562F) who both have severe hypotonia and infantile spasms. Pathogenic variants in POLR1A have not previously been associated with infantile spasms, and the role of POLR1A in central nervous system development is unknown. Infantile spasms (IS) are a rare and often treatment-refractory type of epilepsy frequently associated with poor neurodevelopmental outcomes. Research into improving therapeutics would be greatly enhanced with proper animal models of IS. To understand how this particular POLR1A variant causes infantile spasms and hypotonia in our human patients, we will use CRISPR/Cas9 to generate a mouse model with the identical variant. We hope this work will lead to identification of therapeutic targets for POLR1A-related neurodevelopmental abnormalities, as well as a model in which to test potential therapies.