Collection And Analysis of PAX8 Variants and Their Impact on Protein Function Via ClinVar and AlphaMissence

Abstract: 

This study analyzes the genetic influences of paired box gene 8 (PAX8) on Hashimoto’s thyroiditis (HT) by examining PAX8 protein structure and function. Using a computational approach by comparing data from ClinVar and AlphaMissence databases, PAX8 variants and their impact on protein function were classified. The research identified 33 PAX8 genetic variants associated with HT, focusing on their pathogenicity. ClinVar was used to document variants, while AlphaMissense provided an additional layer of classification. Molecular models were created to visualize how these mutations affect protein structure, using data from Protein Data Bank and AlphaFold, refined through PyMol and InkScape. Findings revealed that 62.5% of pathogenic mutations were concentrated in the PAI subdomain of the Paired Box Domain, with a smaller portion in the RED subdomain. These regions are crucial for DNA recognition, and mutations here likely disrupt the gene’s ability to activate promoters essential for thyroid function. Interestingly, ClinVar and AlphaMissense sometimes conflicted in their classifications but agreed on many pathogenic variants. This study highlights the critical role of PAX8 mutations in HT development, particularly in protein stabilization. By improving the understanding of these genetic influences, this research could contribute to more precise diagnostic tools and targeted treatments for HT.