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An inclusive study of deleterious missense PAX9 variants using user-friendly tools reveals structural, functional
Prashant Ranjan1, Parimal Das1
1Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Abstract:
Mutations in the PAX9 are responsible for non-syndromic tooth agenesis in humans, although their structural and functional consequences on protein phenotype, stability, and posttranslational modifications (PTMs) have not yet been adequately investigated. This in silico study focuses on retrieving the six most deleterious mutations (L21P, R26W, R28P, G51S, I87F, and K91E) of PAX9 that has been linked to severe oligodontia. Several computational algorithm methods were used to determine the deleterious effects of PAX9 mutations. Analysis of gene ontology, protein interactions, and PTMs indicated significant functional changes caused by PAX9 mutations. The structural superimposition of the wild-type and mutant PAX9 variants revealed structural changes in locations that were present in the structures of all six variations. The conserved domain analysis revealed that the areas shared by all six variations contained unique sections that lacked DNA binding or protein-protein interaction sites, suggesting prospective drug target sites for functional restoration. The protein-protein interaction network showed KDM5B as PAX9's strongest interacting partner similar to MSX1. The PAX9 protein's structural conformations, compactness, stiffness, and function may all be impacted by changes, according to MD simulations. In addition, research on cell lines and animal models may be valuable in establishing their specific roles in functional annotations.
Insights
Mutations in the paired box 9 (PAX9) gene cause tooth agenesis. This study identified six harmful PAX9 mutations, revealing structural changes and potential drug targets for restoring tooth development.
Area of Science:
- Genetics
- Molecular Biology
- Bioinformatics
Background:
- Mutations in the PAX9 gene are a known cause of non-syndromic tooth agenesis.
- The structural and functional impacts of these PAX9 mutations, including protein stability and posttranslational modifications (PTMs), remain poorly understood.
Purpose of the Study:
- To computationally investigate the structural and functional consequences of six deleterious PAX9 mutations linked to severe oligodontia.
- To identify potential therapeutic targets for functional restoration.
Main Methods:
- In silico analysis using computational algorithms to assess mutation effects.
- Gene ontology, protein interaction, and PTM analyses.
- Structural superimposition, conserved domain analysis, and molecular dynamics (MD) simulations.
Main Results:
- Six deleterious PAX9 mutations (L21P, R26W, R28P, G51S, I87F, K91E) were identified, causing significant functional changes.
- Structural analysis revealed consistent changes across all mutants, highlighting unique regions lacking DNA binding or protein-protein interaction sites.
- KDM5B was identified as a key interacting partner of PAX9, alongside MSX1.
Conclusions:
- PAX9 mutations significantly alter protein structure, stability, and function, potentially impacting DNA binding and protein interactions.
- The identified unique regions in conserved domains represent potential drug targets for treating tooth agenesis.
- Further in vitro and in vivo studies are recommended to validate these findings.
