X-linked lymphoproliferative disease (also known as "Duncan's disease":86 or "Purtilo syndrome") 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 signalling 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.
The SAP protein is important in the signalling events that activate T- and NK-cells 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.
A second form is associated with XIAP.
Some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease.
Strangely, in boys with X-linked lymphoproliferative disorder, there is an inability to mount an immune 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.
Patients produce insufficient numbers of CD27 memory B cells.
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