Computational Analysis of Epilepsy Mutations in the Kinesin Motor Domain of KIF1A

Résumé

Background: The Kinesin Family Member-1A (KIF1A) gene encodes a motor protein crucial for axonal transport and synaptic vesicle transport in neurons. KIF1A mutations are associated with neurological disorders, including Hereditary Spastic Paraplegia, Intellectual Disability, and Autism. Mutations in KIF1A have been found to increase the hyperactivity of the motor protein, altering the axonal transport of synaptic vesicles precursors. Mutant KIF1A proteins with hyperactive motor functions have been shown to increase excitatory synaptic transmission, suggesting a potential role in the development of epileptic seizures. Aim: This study emphasizes on the computational analysis of previous reported missense mutations of KIF1A causing epilepsy. Methodology: Comparative protein models of normal and all selected mutations (R13C and A85D were identified in Japanese patient, T99M, T258M and R316W were found in Korean patients) was prepared. Pathogenic prediction was performed using Meta-SNP and PREDICT SNP, Phylogenetic analysis was performed using MEGA software and molecular docking by using previously discovered drugs was performed using PyRx tool. Results: All mutations were predicted highly pathogenic and reported to cause epilepsy with other associated symptoms. Compounds with highest binding affinity were selected for docking which binds with the receptor making it a successful docking. Phylogenetic analysis revealed the changes in their conserved regions making these mutations pathogenic. Conclusion:  This study gives a time and cost-effective analysis of KIF1A gene causing epilepsy and genetic mutations that play a key role in development and cause of disease.