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<p>The SMARCB1 gene codes for a key element of the SWI/SNF chromatin-modifying complex, which plays a vital role in controlling gene expression by modifying chromatin architecture. Alterations in SMARCB1 have been linked to several neurological disabilities, including schwannomatosis, a condition marked by the formation of numerous benign tumors affecting the nerve sheaths. Present study&#xa0;explore the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) within the SMARCB1 gene on its protein structure and functionality. We utilized both sequence-based and structure-oriented predictive models, followed by molecular dynamics simulations to examine their influence on the stability of protein&#xa0;and dynamic behaviour. The study focused on three key mutations: R60S, R190W, and I237M. The R190W mutation emerged as particularly significant, leading to increased protein compactness and stability due to enhanced hydrophobic interactions, although conformational flexibility&#xa0;was reduced. The R60S mutation was associated with destabilization of the protein structure, increasing solvent exposure and reducing hydrogen bond stability, potentially impairing the protein's function. The I237M mutation had a relatively mild impact, with only subtle changes observed in protein dynamics. These findings highlight the diverse impacts of different nsSNPs on SMARCB1, with the potential to contribute to various pathologies, including Schwannomatosis and other related disorders. This study highlights the necessity for additional experimental testing to confirm&#xa0;these computational findings and gain a deeper understanding of the molecular processes through which these mutations contribute to disease. The present&#xa0;comprehensive approach provides significant knowledge regarding the connection between SMARCB1 structure and function, providing&#xa0;the groundwork for potential therapeutic strategies targeting these key mutations.</p>

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Predicting high-risk clinical missense variants of SMARCB1 in rare neurogenetic disorder schwannomatosis (nerve tumor) through sequence, structure, and molecular dynamics analyses

  • 期刊论文

  • 发表日期：

    2025年2月20日

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  • Mitesh Patel,
  • Reem Binsuwaidan,
  • Malvi Surti,
  • Nawaf Alshammari,
  • Angum M. M. Ibrahim,
  • Mohd Adnan

摘要

The SMARCB1 gene codes for a key element of the SWI/SNF chromatin-modifying complex, which plays a vital role in controlling gene expression by modifying chromatin architecture. Alterations in SMARCB1 have been linked to several neurological disabilities, including schwannomatosis, a condition marked by the formation of numerous benign tumors affecting the nerve sheaths. Present study explore the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) within the SMARCB1 gene on its protein structure and functionality. We utilized both sequence-based and structure-oriented predictive models, followed by molecular dynamics simulations to examine their influence on the stability of protein and dynamic behaviour. The study focused on three key mutations: R60S, R190W, and I237M. The R190W mutation emerged as particularly significant, leading to increased protein compactness and stability due to enhanced hydrophobic interactions, although conformational flexibility was reduced. The R60S mutation was associated with destabilization of the protein structure, increasing solvent exposure and reducing hydrogen bond stability, potentially impairing the protein's function. The I237M mutation had a relatively mild impact, with only subtle changes observed in protein dynamics. These findings highlight the diverse impacts of different nsSNPs on SMARCB1, with the potential to contribute to various pathologies, including Schwannomatosis and other related disorders. This study highlights the necessity for additional experimental testing to confirm these computational findings and gain a deeper understanding of the molecular processes through which these mutations contribute to disease. The present comprehensive approach provides significant knowledge regarding the connection between SMARCB1 structure and function, providing the groundwork for potential therapeutic strategies targeting these key mutations.