Computational insights into missense mutations in HTT gene causing Huntington's disease and its interactome networks.

Abstract

Huntington's disease is a rare neurodegenerative illness of the central nervous system that is inherited in an autosomal dominant pattern. Mutant huntingtin proteinis produced as a result of enlargement of CAG repeat in the N-terminal of the polyglutamine tract. Herein, we aim to investigate the mutations and their effects on the HTT gene and its genetic variants. Additionally, the protein-protein interaction of HTT with other proteins and receptor-ligand interaction with the three-dimensional structure of huntingtin proteinwere identified. A comprehensive analysis of the HTT interactome and protein-ligand interaction has been carried out to provide a global picture of structure-function analysis of huntingtin protein. Mutations were analyzed and mutation verification tools were used to check the effect of mutation on protein function. The results showed, mutations in a single gene are not only responsible for causing a particular disease but may also cause other hereditary disorders as well. Moreover, the modification at the nucleotide level also cause the change in the specific amino acid which may disrupt the function of HTT and its interacting proteins contributing in disease pathogenesis. Furthermore, the interaction between MECP2 and BDNF lowers the rate of transcriptional activity. Molecular docking further confirmed the strong interaction between MECP2 and BDNF with highest affinity. Amino acid residues of the HTT protein, involved in the interaction with tetrabenazine were N912, Y890, G2385, and V2320. These findings proved, tetrabenazine as one of the potential therapeutic agent for treatment of Huntington's disease. These results give further insights into the genetics of Huntington's disease for a better understanding of disease models which will be beneficial for the future therapeutic studies.