The impact of genetic variants on kinesin motor proteins and the link to neurological disorders

Open Access
Erdman, Marcus Orion
Area of Honors:
Biomedical Engineering
Bachelor of Science
Document Type:
Thesis Supervisors:
  • William Hancock, Thesis Supervisor
  • William Hancock, Honors Advisor
  • Peter Butler, Faculty Reader
  • Justin Lee Brown, Faculty Reader
  • kinesin
  • neurological disorder
  • mutation
  • genomics
Axonal transport driven by kinesin motor proteins is essential for the function of neurons and the transport of vesicles and organelles toward the synaptic cleft. Kinesins hydrolyze ATP as they move in a stepping motion along microtubules, and defects in their function can result in neuron malfunction and neurological disorders. Non-conservative missense mutations in the motor domain of a specific axonal kinesin, KIF1A/UNC-104, have been shown to have adverse effects on the motor speed and the distance moved by the motor prior to dissociation from the microtubule. The goal of this study is to characterize the potential pathogenicity of missense variants of KIF1A/UNC-104. Several key variants have been identified in the literature as mutations that may have a direct causal relationship with neurodegenerative, neuromuscular, and other nervous system disorders. Three missense mutations, S69L, T99M, and A255V that have shown disease association were functionally examined through gliding and single molecule motility assays to assess the impact of the mutations. In single-molecule assays, wild type UNC-104 travelled an average of 2.40 μm at a velocity of 2.32 μm/s before dissociation, providing a baseline to assess mutants. The mutant kinesins were unable to achieve this rapid, processive motility and were shown to have defective tight-binding states while retaining their unique weak-binding functionality. To add to the number of mutants in the literature and to determine a larger set of variants that are associated with disease, the MyCode database of Geisinger Health System was employed. The database was queried to determine patients in the population who have mutations in the motor domain of several axonal kinesins beyond KIF1A/UNC104 that also have been linked to neurological disorders. Using the arguments of the disease association and the decrease in functionality, it is hoped that this study will identify novel pathogenic variants.