CD40Lbase, mutation database for X-linked hyper-IgM syndrome (XHIM)

Jouni Väliaho1, Luigi D. Notarangelo2, Manuel C. Peitsch3, and Mauno Vihinen1

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

X-linked hyper-IgM syndrome (XHIM) is an immunodeficiency caused by mutations in the gene coding for CD40 antigen ligand (CD40L). Patients with XHIM have recurrent infections and very low levels of serum IgG, IgA, and IgE, with normal or elevated IgM. 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.

CD40 ligand belongs to the tumor necrosis factor superfamily. It is a type II membrane protein and it consist of four distinct structural domains, which are from the N-terminus, the intracytoplasmic domain (IC), transmembrane domain (TM), extracellular unique domain (ECU), and tumor necrosis factor homology domain (TNFH). The CD40 ligand protein is coded by the CD40LG gene (also known as TNFSF5), which consists of five exons. There is no homology in the positions of exons between CD40LG and any of the known genes from the TNF family, but in all these genes the sequence encoding the receptor binding domain is located in the last exon. The structural consequences of the mutations in the TNFH domain have been studied based on crystallographic structure.

CD40Lbase (2) (http://www.uta.fi/imt/bioinfo/CD40Lbase/) lists 88 mutation entries. The localisation of the mutations on the gene and protein for CD40L 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. CD40Lbase provides direct link to the SRS search engine at EBI for further analysis.

Most of the mutations (52) are in the TNFH domain (23 missense and 8 nonsense mutations, 8 frameshift insertions, 12 frameshift deletions, and 1 inframe deletion). There are 12 mutations in the ECU domain (1 missense, 1 silent, and 3 nonsense mutations, 3 frameshift insertions, and 4 frameshift deletions), and 4 mutations in the TM domain (missense mutations). The rest are intron, upstream, and downstream mutations, and gross genomic deletions.

References

  1. Riikonen, P. and Vihinen, M. (1999) Bioinformatics, (in press).
  2. Notarangelo, L. D. and Peitsch, M. C. (1996) Immunology Today, 17, 511-6.