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<p>Interleukin-2-inducible T-cell kinase (ITK), a mammalian non-receptor tyrosine kinase, shows the highest level of expression in T lymphocytes. Mutations that cause defective ITK are associated with some diseases and cancers. The aim of this study is to bioinformatically analyze harmful missense single nucleotide polymorphisms (SNPs) in the coding region of the human <i>ITK</i>. The functional analysis of 461 missense SNPs in <i>ITK</i> by 10 tools illustrated that 49 substitutions arising from 45 SNPs are damaging. MUpro, I-Mutant, and INPS-MD showed that 36 amino acid substitutions decrease ITK stability. ConSurf revealed that the positions of 28 amino acids of high-risk SNPs were in extremely conserved sites. According to the NetSurf-3 prediction, most of SNPs were located in buried positions. GeneMANIA showed that ITK had direct physical interactions with 17 other proteins. Based on PhosphoSitePlus results, Y180C and T274P substitutions disrupt phosphorylation sites, and K391R modifies ubiquitination pattern of ITK. HOPE server determined the effect of SNPs on the tertiary structure of ITK. The impact of mutations on interactions between ATP and residues in ITK’s binding pocket were analyzed through AlphaFold 3. Docking analysis exhibited that mutations in ITK’s ligand binding site can change interactions between residues and a specific ITK inhibitor. According to conservation, interaction with ligand, and protein stability parameters, among 49 deleterious substitutions, G370V, V377M, V377A, K391R, V419A, E436K, G441S, G441R, and G441D seem to be more high-risk. Information obtained from in silico methods is beneficial for large population studies to confirm a relationship between deleterious SNPs and diseases.</p>

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Identification of Deleterious Missense Single Nucleotide Polymorphisms in Human ITK Gene: An In Silico Study

  • 期刊论文

  • 发表日期：

    2025年7月14日

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  • Fatemeh Tupchi,
  • Parisa Farrokh,
  • Taghi Lashkarbolouki

摘要

Interleukin-2-inducible T-cell kinase (ITK), a mammalian non-receptor tyrosine kinase, shows the highest level of expression in T lymphocytes. Mutations that cause defective ITK are associated with some diseases and cancers. The aim of this study is to bioinformatically analyze harmful missense single nucleotide polymorphisms (SNPs) in the coding region of the human ITK. The functional analysis of 461 missense SNPs in ITK by 10 tools illustrated that 49 substitutions arising from 45 SNPs are damaging. MUpro, I-Mutant, and INPS-MD showed that 36 amino acid substitutions decrease ITK stability. ConSurf revealed that the positions of 28 amino acids of high-risk SNPs were in extremely conserved sites. According to the NetSurf-3 prediction, most of SNPs were located in buried positions. GeneMANIA showed that ITK had direct physical interactions with 17 other proteins. Based on PhosphoSitePlus results, Y180C and T274P substitutions disrupt phosphorylation sites, and K391R modifies ubiquitination pattern of ITK. HOPE server determined the effect of SNPs on the tertiary structure of ITK. The impact of mutations on interactions between ATP and residues in ITK’s binding pocket were analyzed through AlphaFold 3. Docking analysis exhibited that mutations in ITK’s ligand binding site can change interactions between residues and a specific ITK inhibitor. According to conservation, interaction with ligand, and protein stability parameters, among 49 deleterious substitutions, G370V, V377M, V377A, K391R, V419A, E436K, G441S, G441R, and G441D seem to be more high-risk. Information obtained from in silico methods is beneficial for large population studies to confirm a relationship between deleterious SNPs and diseases.