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<p>OPA1 protein is a dynamin-related GTPase that play a crucial role in regulating mitochondrial dynamics, cristae integrity, energetics, and mtDNA maintenance. Mutations in the <i>OPA1</i> gene lead to a diverse spectrum of neurodegenerative disorders, most notably autosomal dominant optic atrophy (ADOA). The majority of the identified non-synonymous single nucleotide polymorphisms (nsSNPs) in this gene are located within the GTPase domain of the OPA1 protein. The aim of this study was to categorize the most pathogenic missense variants located in this domain and predict their impact on OPA1 protein structure–function relationship using several computational analysis tools. Out of 850 nsSNPs identified in <i>OPA1</i> gene from the NCBI database, 262 were mapped to the GTPase domain and were further selected and analyzed. Of these, 67 missense variants were identified as the most pathogenic based on 12 prediction tools. Among these pathogenic variants, 44 were located at highly conserved residues and predicted to cause a significant disruption in protein function. Notably, five variants (D296H, R324H, P400S, P400L, and G401D) clustered within crucial consensus sequences. In silico analysis of 3-D structural models built for these 44 conserved variants revealed significant conformational changes in mutant proteins containing L396P and L434P variants compared to native OPA1 protein. Furthermore, molecular docking analysis showed altered GTP binding in four mutated models (E306D, G401D, G439V, and P400L) relative to the native protein, which could affect protein function. Significantly, three of these variants (P400L, G401D, and G439V) have been previously reported in patients with ADOA.</p>

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In silico analysis of the impact of missense variants within the GTPase domain of the human OPA1 gene: effect on OPA1 protein structure and its interaction with GTP ligand

  • 期刊论文

  • 发表日期：

    2025年7月26日

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  • Dalel Mhiri,
  • Nidhal Tarhouni,
  • Bassem Khemakhem,
  • Faiza Fakhfakh

摘要

OPA1 protein is a dynamin-related GTPase that play a crucial role in regulating mitochondrial dynamics, cristae integrity, energetics, and mtDNA maintenance. Mutations in the OPA1 gene lead to a diverse spectrum of neurodegenerative disorders, most notably autosomal dominant optic atrophy (ADOA). The majority of the identified non-synonymous single nucleotide polymorphisms (nsSNPs) in this gene are located within the GTPase domain of the OPA1 protein. The aim of this study was to categorize the most pathogenic missense variants located in this domain and predict their impact on OPA1 protein structure–function relationship using several computational analysis tools. Out of 850 nsSNPs identified in OPA1 gene from the NCBI database, 262 were mapped to the GTPase domain and were further selected and analyzed. Of these, 67 missense variants were identified as the most pathogenic based on 12 prediction tools. Among these pathogenic variants, 44 were located at highly conserved residues and predicted to cause a significant disruption in protein function. Notably, five variants (D296H, R324H, P400S, P400L, and G401D) clustered within crucial consensus sequences. In silico analysis of 3-D structural models built for these 44 conserved variants revealed significant conformational changes in mutant proteins containing L396P and L434P variants compared to native OPA1 protein. Furthermore, molecular docking analysis showed altered GTP binding in four mutated models (E306D, G401D, G439V, and P400L) relative to the native protein, which could affect protein function. Significantly, three of these variants (P400L, G401D, and G439V) have been previously reported in patients with ADOA.