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ORIGINAL RESEARCH article

Front. Genet.
Sec. Computational Genomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1517707
This article is part of the Research Topic Genetic Horizons: Exploring Genetic Biomarkers in Therapy and Evolution with the Aid of Artificial Intelligence View all articles

A Structural Genomics Approach to Investigate Dystrophin Mutations and their Impact on the Molecular Pathways of Duchenne Muscular Dystrophy

Provisionally accepted
Abdelbaset Mohamed Elasbali Abdelbaset Mohamed Elasbali 1Waleed Abu Al-Soud Waleed Abu Al-Soud 1Mohd Adnan Mohd Adnan 2Anas Shamsi Anas Shamsi 3*Md. Imtaiyaz Hassan Md. Imtaiyaz Hassan 4*
  • 1 Jouf University, Sakakah, Al Jawf, Saudi Arabia
  • 2 University of Hail, Ha'il, Hail, Saudi Arabia
  • 3 Ajman University, Ajman, Ajman, United Arab Emirates
  • 4 Jamia Millia Islamia, New Delhi, India

The final, formatted version of the article will be published soon.

    Background: Dystrophin is a key protein encoded by the DMD gene, serves as a scaffold linking the cytoskeleton to the extracellular matrix that plays a critical role in muscle contraction, relaxation, and structural integrity. Mutations, particularly single-point amino acid substitutions, can lead to dysfunctional Dystrophin, causing muscular dystrophies, with Duchenne muscular dystrophy (DMD) being the most severe form.Objective: This study aimed to evaluate the effects of 184 single-point amino acid substitutions on the structure and function of Dystrophin using computational approaches.Methods: A suite of computational tools was used to predict the impact of amino acid substitutions on protein stability, solubility, and function. Pathogenic potential was assessed using disease phenotype predictors and CADD scores, while allele frequency data from gnomAD contextualized mutation prevalence. Additionally, aggregation propensity, frustration analysis, and post-translational modification sites were analyzed for functional disruptions.Of the 184 substitutions analyzed, 50 were identified as deleterious, with 41 predicted to be pathogenic. Seventeen mutations were localized in the Calponin-homology (CH) 1 domain, a critical functional region of Dystrophin.Six substitutions (N26H, N26K, G47W, D98G, G109A, and G109R) were predicted to decrease protein solubility and were located in minimally frustrated regions, potentially compromising Dystrophin functionality and contributing to DMD pathogenesis.This study provides novel insights into the molecular mechanisms of DMD, highlighting specific mutations that disrupt Dystrophin's solubility and function. These findings could inform future therapeutic strategies targeting Dystrophin mutations to address DMD pathogenesis.

    Keywords: Deleterious mutations, Duchenne muscular dystrophy, Dystrophin, Neuromuscular Diseases, personalized medicine, structural genomics

    Received: 28 Oct 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Elasbali, Abu Al-Soud, Adnan, Shamsi and Hassan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Anas Shamsi, Ajman University, Ajman, Ajman, United Arab Emirates
    Md. Imtaiyaz Hassan, Jamia Millia Islamia, New Delhi, India

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