Browsing by Author "Amina Khawar"

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    Computational analysis predicting deleterious variants in fbxo31 gene
    (UMT, Lhr, 2023) Amina Khawar
    Intellectual developmental disorder is an autosomal recessive disorder characterized by severely below overall intellectual functioning together with abnormalities in adaptive behavior. It is often associated with depression, autism, hyperactivity disorder, and attention deficit. It is mainly caused due to mutations in the FBXO31 gene. The FBXO31 gene is located on chromosome 16 contains nine exons and encodes for 539 amino acid proteins and works as a centrosomal E3 ubiquitin ligase together with SKP1 and Cullin-1. The complex of FBXO31, SKP1 and Cullin-1 is significant for axonal identity and neuronal morphogenesis. Mutations in the FBXO31 gene lead to the deregulation of this complex and its subunits resulting in intellectual disability. In this study, bioinformatic approach has been used to predict the highly pathogenic missense and splice site variants of the FBXO31 gene that caused the deregulation of Skp/Cullin/F-box (SCF) ubiquitin E3 ligase complex. For the screening of pathogenic variants of FBXO31 gene multiple analysis such as missense, stability, post translational modification, conservation, and splice site analysis was done. The pathogenic variants were retrieved from gnomAD and analyzed by missense and splice site variation analysis. For missense analysis, CADD, CAPICE and metaSNP tools were used. Pathogenicity and stability of the variants analyzed by web tools predicted 89 highly pathogenic missense variants and among these 89 variants, 8 were highly destabilizing on the basis of Gibbs Free energy predicted by Duet and DynaMut. The functional analysis of deleterious variants done by Mutpred tool and it was predicted that 85 pathogenic variants disturbing the function of the protein. Moreover, UCSF chimera utilized to check the clashes and 21 deleterious variants clashing with their surrounding residues in the structure of protein. Furthermore, Consurf tool utilized to check the impact of the pathogenic variants on the conserved regions of the protein and 42% gene predicted as conserved. PTM analysis done by utilizing Scan Prosite and NetSurf2.0 and it was predicted that 4/89 pathogenic variants are disturbing the post translational modification sites of FBXO31 gene. Moreover, splice sites analysis was also done by SPiCE v2.1, Splice AI and Mutation Taster and 6 pathogenic variants predicted to affect the splicing mechanism of the FBXO31 gene. This study proved that these variations have a significant role in the deregulation of FBXO31 complex that leads to intellectual disability. FBXO31 deleterious variants predicted in this study can be further analyzed on cell assays.