Date of Award

Summer 8-16-2024

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Robert W Burgess

Second Committee Member

Gregory A Cox

Third Committee Member

Lucy Liaw

Additional Committee Members

Benjamin L King

Joel H Graber

Abstract

Rare diseases, though individually uncommon, collectively affect approximately 350 million people worldwide, and there are no effective treatments for most rare diseases. Rare diseases also present unique research challenges. The low number of patients affected by any rare disease renders methods applied in the study of more common diseases, such as genome wide association studies or large patient tissue databases, less effective or impossible to create. Therefore, animal models of disease, particularly mice, have an important role in understanding and developing treatments for rare diseases. This work examines several cases in which mice provide valuable insight into human disorders that would otherwise be unavailable. We characterize an allelic series of spontaneous mutations in retinoid-related orphan receptor beta, a gene that encodes a poorly understood orphan receptor relevant to idiopathic generalized epilepsy 15. We describe a novel mouse model for human NADK2 deficiency that recapitulates metabolic and biochemical pathophysiology of patients. We perform a validation study for a candidate disease-modifying gene identified by a rare disease genome wide association study for Charcot-Marie-Tooth disease type 1A. Finally, we assess the contribution of genetic background to variability in Charcot-Marie-Tooth disease type 2D phenotypes using genetically- diverse strains of inbred mice. The work concludes with a discussion of how large high- throughput sequencing datasets from mouse models may be used to stratify models into therapeutic treatment groups and provide further insight into rare inherited peripheral neuropathies. Together, the results described herein contribute to knowledge of several rare diseases and illustrate the role of mouse models in the study of rare neurological disease.

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