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Hum Mutat. 2015 Jun;36(6):638-47. doi: 10.1002/humu.22791. Epub 2015 Apr 27.

Characterization of all possible single-nucleotide change caused amino acid substitutions in the kinase domain of Bruton tyrosine kinase.

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BioMediTech, University of Tampere, Tampere, Finland.
Present address is HiDucator Ltd., Erämiehentie 2 E 22, Kangasala FI-36200, Finland.
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Research Unit, Tampere University Hospital, Tampere, Finland.


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.


BTK; Bruton tyrosine kinase; X-linked agammaglobulinemia; XLA; kinase domain; mutation; protein structure

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