¹Institute of Medical Technology, University of Tampere, P. O. Box 607, FIN-33101-Tampere, Finland, fax. +358-3-215 7710, e-mail ltmavi{at}uta.fi,
²Department of Pediatrics, University of Brescia, Brescia, Italy, e-mail notarang{at}master.cci.unibs.it
³GlaxoWellcome Experimental Research S.A., 16, chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland, fax. +41-22-884 8650, e-mail mcp13936{at}ggr.co.uk

JAK3 (Janus kinase 3) deficiency is an autosomal recessive severe combined immunodeficiency (SCID) caused by mutations in the gene coding for Janus kinase 3 protein. Patients with JAK3 deficiency have severely reduced T-cell development and B-cell function. JAK3 deficiency is characterized by the absence of circulating mature T lymphocytes and NK cells, normal to elevated numbers of nonfunctional B lymphocytes, and marked hypoplasia of lymphoid tissues. Hereditary immunodeficiency-causing mutations are collected into ImmunoDeficiency mutatation databases (IDbases), which are available at http://www.uta.fi/imt/bioinfo/. IDbases contain mutation data, both published and directly submitted information. For each patient is given following information (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 (1), 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.

JAK3 belongs to the JAK family of related cytoplasmic protein tyrosine kinases. The JAK family proteins consist of five distinct structural domains, which are from the C-terminus, the C-terminal kinase domain (termed JAK homology 1, JH1), a more proximal kinase-like domain (JH2) whose function is not defined, and five other N-terminal regions (JH3-JH7) (2). The JAK3 protein is coded by the JAK3 gene, which consists of 20 exons spanning approximately 15 kb.

JAK3base (http://www.uta.fi/imt/bioinfo/JAK3base/) lists ten mutation entries. All of them are from unrelated families showing 14 unique molecular events. The localisation of the mutations on the gene and protein for JAK3 can be analysed by clicking sequences. 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. JAK3base provides direct link to the SRS search engine at EBI for further analysis.

Most of the mutations are in the JH2 domain (5 mutations), JH3 domain (3 mutations), and JH1 domain (2 mutations). One mutation is in the JH7 domain, JH4 domain and intervening region between JH2 and JH1 domains. All kinds of mutation types occur in JAK3 protein: 4 missense mutations, 3 nonsense mutations, 2 deletions, 1 insertion, and 3 splice site mutations.

References

1. Riikonen, P. and Vihinen, M. (1999) Bioinformatics, (in press).
2. Candotti, F., Villa, A. and Notarangelo, L. D. (1999) In Ochs, H. D. (ed.), Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. Oxford University Press, New York, Oxford, pp. 111-20.