NAR Molecular Biology Database Collection entry number 123
VÄliaho, J1, Smith, C.I.E.2, Vihinen, M.3
1Institute of Medical Technology, FIN-33014 University of Tampere, Finland
2Center for BioTechnology, Department of Biosciences at Novum, Karolinska Institute, S-14157 Huddinge, Sweden
3Research Unit, Tampere University Hospital, FIN-33520 Tampere, Finland

Database Description

X-linked agammaglobulinemia (XLA; OMIM 300300) is an immunodeficiency caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). Patients with XLA have decreased number of mature B cells and lack of all immunoglobulin isotypes causing susceptibility to severe bacterial infections. Hereditary immunodeficiency-causing mutations are collected into ImmunoDeficiency mutation databases (IDbases) (1), which are available at IDbases contain mutation data, both published and directly submitted information. For each patient the following information is given (when available): The identification of the entry and plain English description of the mutation are followed by reference and formal characterisation of the mutation. Last are the various parameters from the patient. IDbases are maintained with MUTbase program suite (2) which provides an easy, interactive and quality controlled submission of information to mutation databases. For further study of the databases on the World Wide Web, a number of tools are provided. The program package also writes and updates a large number of Web pages e.g. about distribution and statistics of disease-causing mutations, and changes in restriction patterns. The BTK is crucial for signalling in B cells. It belongs to the Tec family of cytoplasmic protein tyrosine kinases. The Tec family proteins consist of five distinct structural domains, which are from the N-terminus, a pleckstrin homology (PH) domain, a Tec homology (TH) domain, a Src homology 3 (SH3) domain, a SH2 domain, and the catalytic kinase domain. Mutations in all the five domains cause XLA. The structural consequences of the mutations have been studied based on crystallographic and NMR structures as well as computer-aided molecular modelling.

Recent Developments

BTKbase (3,4) ( lists mutation entries of 855 patiens from 746 unrelated families showing 512 unique molecular events. The localisation of the mutations on the gene and protein for BTK can be analysed by clicking sequences on Web pages. This can be performed either on genomic, cDNA or amino acid level. Several tables provide information about the distribution of mutations and several clickable pages are related to modifications in restriction pattern. BTKbase provides direct link to the SRS search engine for further analysis. The distribution of the mutations in the five structural domains is approximately according to the length of the domains, except for the TH domain. The most frequently affected sites are CpG dinucleotides. Many of the mutations affect functionally significant, conserved residues. The majority of the missense mutations in the PH domain are in the putative binding region. In the TH domain the missense mutations affect Zn2+ binding.


1. Vihinen, M., Arredondo-Vega, F. X., Casanova, J. L., Etzioni, A., Giliani, S., HammarstrÖm, L., Hershfield, M. S., Heyworth, P. G., Hsu, A. P., LÄhdesmÄki, A., Lappalainen, I., Notarangelo, L. D., Puck, J. M., Reith, W., Roos, D., Schumacher, R. F., Schwarz, K., Vezzoni, P., Villa, A., VÄliaho, J. and Smith, C. I. (2001) Primary immunodeficiency mutation databases. Adv Genet, 43, 103-188.
2. Riikonen, P. and Vihinen, M. (1999) MUTbase: maintenance and analysis of distributed mutation databases. Bioinformatics, 15, 852-859.
3. Vihinen, M., Brandau, O., Branden, L. J., Kwan, S. P., Lappalainen, I., Lester, T., Noordzij, J. G., Ochs, H. D., Ollila, J., Pienaar, S. M., Riikonen, P., Saha, B. K. and Smith, C. I. E. (1998) BTKbase, mutation database for X-linked agammaglobulinemia (XLA). Nucleic Acids Res, 26, 242-247.
4. Vihinen, M., Kwan, S. P., Lester, T., Ochs, H. D., Resnick, I., VÄliaho, J., Conley, M. E. and Smith, C. I. (1999) Mutations of the human BTK gene coding for bruton tyrosine kinase in X- linked agammaglobulinemia. Hum Mutat, 13, 280-285.

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