X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency specific to infection by Epstein-Barr virus (EBV). Rather than self-limited infectious mononucleosis following primary exposure to EBV, affected boys develop uncontrolled proliferation of EBV-transformed B cells, often culminating in fatal lymphoma. XLP is therefore a genetic model for the EBV-induced lymphomas seen in MDS patients and in organ transplant recipients. The nature of the inherited defect in XLP patients is unknown, and no consistent immunological abnormalities have been demonstrated in these children prior to EBV infection. We propose experiments aimed at isolating the XLP disease gene by a """"""""positional cloning"""""""" approach. The XLP gene has been mapped to a genetic locus at chromosome Xq25, and three unrelated patients with homozygous germline deletions of approximately 2 megabases at that locus have been reported. Boys who are homozygous for this large deletion on the X chromosome have no clinical abnormalities other than XLP, suggesting that no other """"""""critical"""""""" genes are present within that chromosomal locus. We identified the first of three known genomic markers within the common region deleted-in all three XLP patients, and have used these as starting points in establishing a yeast artificial chromosome (YAC) contig spanning the deletion. To identify potential transcripts within this region, we are using Exon Amplification, a highly sensitive technique developed to """"""""trap"""""""" exons from genomic DNA. Potential exons will be used to screen cDNA libraries and will also be useful as markers in ordering the YAC contig. Candidate cDNAs will be screened by sequencing, tissue distribution of expression, and analysis for mutations in XLP patients who do not have gross chromosomal deletions. The identification of the XLP disease gene will allow biochemical and functional experiments aimed at defining its role in the growth control of EBV-transformed lymphoid cells.
| Nichols, K E; Harkin, D P; Levitz, S et al. (1998) Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A 95:13765-70 |
