X-linked lymphoproliferative disease is a lymphoproliferative disorder. There is a mutation on the X chromosome that has been found to be associated with a T and NK cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25. At this position, there is a deletion in the SH2D1A gene, which codes for an SH2 domain on a signal transducing protein called SLAM-associated protein (SAP).

The term SH2 domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signaling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity.^[1]

The SAP protein is important in the signaling events that activate T and NK cells^[2] because it functions as an intracellular adapter that transduces T and NK cell activation. Normally, the SAP protein is expressed in the cytoplasm of T and NK cells, where it binds to the cytoplasmic domain of the surface receptor called Signaling Lymphocyte Activation Molecule (SLAM). This binding initiates a signal transduction pathway, which results in the modulation of IFN-γ. A deletion in the SH2D1A gene leads to a non-functional SH2 domain on the SAP protein, which means it is unable to bind to the SLAM molecule, leading to a lack of modulation of IFN-γ, causing uncontrolled cell proliferation.

Strangely, in boys with X-linked lymphoproliferative disorder there is an overwhelming T-cell mediated response to the Epstein-Barr virus (EBV), which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined.^[3]