• Muneeza Qayyum Khan, Hira Mubeen, Zohaira Qayyum Khan, Ammara Masood, Asma Zafar, Javed Iqbal Wattoo, and Alim Un Nisa.
• Department of Biotechnology, University of Central Punjab, Lahore, Pakistan.
• Ir J Med Sci. 2023 Jun 1; 192 (3): 143514451435-1445.

BackgroundHuntington's disease is a rare neurodegenerative illness of the central nervous system that is inherited in an autosomal dominant pattern. Mutant huntingtin protein is produced as a result of enlargement of CAG repeat in the N-terminal of the polyglutamine tract.Aim Of The StudyHerein, 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 protein were identified.MethodsA 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.ResultsThe 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.ConclusionThese 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.© 2022. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.

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