Browsing by Author "Abdul Rafay Pirzada"

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    In-silico analysis of SNP pathogenesis in FAN1, RRM2B, LIG1 and their role in the onset of Huntington’s disease
    (UMT Lahore, 2021-10-08) Abdul Rafay Pirzada
    Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder. The disease is widespread in the European population and is characterized by psychiatric and cognitive abnormalities. It is mainly a monogenic disease and exhibits itself when a threshold of CAG repeats (>40) is surpassed in the HTT gene due to somatic instability. The disease onset is very crucial and controlled by a large number of factors. Recently, certain GWAS studies highlighted important genetic candidates that are part of DNA damage repair machinery and control the age at onset (AAO) of HD. In this study, we employed a computational pipeline to screen out pathogenic nsSNPs of the prominent modifiers of HD: FAN1, RRM2B, and LIG1. The pipeline included a series of online and offline tools backed by consensus, homology, and supervised machine learning algorithms. For FAN1, the adopted tools predicted eight mutations (C64G, Y375N, F379C, R420S, W428R, L841P, W847R, G957V, C1004G) as highly conserved and pathogenic, while on the other hand, the number for RRM2B stayed at seven (W64R, R121C, E131K, F156S, E194G, I224S, F324S) with 4 residues predicted to reside in the active site regions of the protein. Similarly, the SNP screening of LIG1 narrowed seven mutations (M543T, R678H, Y783C, G799D, R871H, R874Q, R879H) as highly damaging for the normal enzymatic functions. Among them, 2 residues belonged to the active site region of the enzyme. The structure-based stability comparisons as well as the molecular docking analysis of the mutants and the WTs also predicted the aforementioned mutants to be highly destabilizing with compromised associations to their respective ligands. Therefore, the alteration of normal protein may bring forth changes in the course of the disease pathway.