A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy
BackgroundDystrophin 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...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1517707/full |
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| author | Abdelbaset Mohamed Elasbali Farah Anjum Osama A. AlKhamees Waleed Abu Al-Soud Mohd Adnan Anas Shamsi Md. Imtaiyaz Hassan |
| author_facet | Abdelbaset Mohamed Elasbali Farah Anjum Osama A. AlKhamees Waleed Abu Al-Soud Mohd Adnan Anas Shamsi Md. Imtaiyaz Hassan |
| author_sort | Abdelbaset Mohamed Elasbali |
| collection | DOAJ |
| description | BackgroundDystrophin 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.ObjectiveThis study aimed to evaluate the effects of 184 single-point amino acid substitutions on the structure and function of Dystrophin using computational approaches.MethodsMany computational tools were 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.ResultsOf 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.ConclusionThis 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. |
| format | Article |
| id | doaj-art-0bed082663df4269b9cd808d5075b76f |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj-art-0bed082663df4269b9cd808d5075b76f2025-02-04T06:31:39ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-02-011610.3389/fgene.2025.15177071517707A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophyAbdelbaset Mohamed Elasbali0Farah Anjum1Osama A. AlKhamees2Waleed Abu Al-Soud3Mohd Adnan4Anas Shamsi5Md. Imtaiyaz Hassan6Department of Clinical Laboratory Science, College of Applied Medical Sciences-Qurayyat, Jouf University, Sakakah, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi ArabiaDepartment of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi ArabiaMolekylärbiologi, Klinisk Mikrobiologi och vårdhygien, Lund, SwedenDepartment of Biology, College of Science, University of Ha’il, Ha’il, Saudi ArabiaCentre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab EmiratesCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, IndiaBackgroundDystrophin 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.ObjectiveThis study aimed to evaluate the effects of 184 single-point amino acid substitutions on the structure and function of Dystrophin using computational approaches.MethodsMany computational tools were 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.ResultsOf 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.ConclusionThis 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.https://www.frontiersin.org/articles/10.3389/fgene.2025.1517707/fulldeleterious mutationsDuchenne muscular dystrophyDystrophinneuromuscular diseasespersonalized medicinestructural genomics |
| spellingShingle | Abdelbaset Mohamed Elasbali Farah Anjum Osama A. AlKhamees Waleed Abu Al-Soud Mohd Adnan Anas Shamsi Md. Imtaiyaz Hassan A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy Frontiers in Genetics deleterious mutations Duchenne muscular dystrophy Dystrophin neuromuscular diseases personalized medicine structural genomics |
| title | A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy |
| title_full | A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy |
| title_fullStr | A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy |
| title_full_unstemmed | A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy |
| title_short | A structural genomics approach to investigate Dystrophin mutations and their impact on the molecular pathways of Duchenne muscular dystrophy |
| title_sort | structural genomics approach to investigate dystrophin mutations and their impact on the molecular pathways of duchenne muscular dystrophy |
| topic | deleterious mutations Duchenne muscular dystrophy Dystrophin neuromuscular diseases personalized medicine structural genomics |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1517707/full |
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