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Unraveling a Novel Missense Mutation (C.A248c) in Wiskott-Aldrich Syndrome Gene by Whole Exome Sequencing: Insights From Dynamic Simulation, Molecular Docking and In-Silico Studies Publisher Pubmed



F Mohammadrezaei FATEMEH ; J Saffarichaleshtori JAVAD ; K Inanloorahatloo KOLSOUM ; R Sherkat ROYA ; M Salehi MANSOOR
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Source: International Immunopharmacology Published:2025


Abstract

Wiskott-Aldrich syndrome (WAS) is an uncommon genetic condition that is inherited via the X chromosome and is caused by mutations in the Wiskott-Aldrich syndrome (WAS) gene. This disease is defined by the presence of persistent thrombocytopenia, eczema, and immunological dysfunction. It is also linked to a higher likelihood of developing autoimmunity and cancer. Using whole-exome sequencing (WES) on the genomic DNA of a family that had two affected members, we detected a new missense hemizygous mutation (c.A248C, Y83S) in the Wiskott-Aldrich syndrome gene (WAS, Xp11.23). The tyrosine residue at position 83 (Y83) changes to serine (S) owing to the missense mutation in exon 2 (c.A248C). Furthermore, a simulation study employing the root mean square fluctuation (RMSF), radius of gyration, and root mean square deviation (RMSD) tools demonstrated that the p.Y83S variant causes changes in the structures of the protein and molecular dynamic characteristics. Since structural alterations have an impact on protein activity, these variations in protein structure may result in a decrease in the stability and function of mutant WASP. In conclusion, this research describes a novel WAS mutation's clinical and molecular characteristics. This mutation causes instability in the WASP protein and reduces its function, and eventually leading to the disease phenotype. © 2025 Elsevier B.V., All rights reserved.
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