Journal
HUMAN MUTATION
Volume 36, Issue 6, Pages 638-647Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.22791
Keywords
BTK; Bruton tyrosine kinase; kinase domain; protein structure; mutation; X-linked agammaglobulinemia; XLA
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Funding
- Sigrid Juselius Foundation
- Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital
- Biocentre Finland
- Faculty of Medicine, Lund University
- Swedish Research Council
- Swedish County Council (ALF-project)
- Swedish Cancer Society
- Ragnar Soderberg Foundation
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Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains the highest number of unique disease-causing variations among the human protein kinases, still it is just 10% of all the possible single-nucleotide substitution-caused amino acid variations (SNAVs). In the BTK kinase domain (BTK-KD) can appear altogether 1,495 SNAVs. We investigated them all with bioinformatic and protein structure analysis methods. Most disease-causing variations affect conserved and buried residues disturbing protein stability. Minority of exposed residues is conserved, but strongly tied to pathogenicity. Sixty-seven percent of variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, whereas in 10% of sites, all the substitutions are tolerated. Results indicate the importance of the entire kinase domain, involvement in numerous interactions, and intricate functional regulation by conformational change. These results can be extended to other protein kinases and organisms.
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