<unk> 1<unk> 1 is caused by mutations in the SH2D1A gene, which is located at position<unk> q25 on the<unk> -chromosome. This gene codes for an SH2 domain on a signal transducing protein called signaling lymphocyte activation molecule (SLAM)-associated protein, or SAP. A variety of mutations have been implicated in<unk> 1 expression, including deletions, single nucleotide changes, and incorrect splicing, although a correlation between the type of mutation and the severity of the disorder has not been established. These defects in SAP fundamentally change the function of two SLAM receptors, 2B4 (CD244) and NTB-A (SLAMF6). Typically, after the receptors bind to their associated ligands, the immunoreceptor tyrosine-based switch motifs (ITSMs) in their cytoplasms are phosphorylated, which activates cell-activating signaling pathways. In an<unk>  patient, the defects in SAP cause these receptors to induce an inhibitory, rather than activating effect. Ligand binding thus fails to activate Natural Killer (NK) and Cytotoxic T cells that typically eliminate EBV infection, leading to cytokine overproduction and tissue damage. 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.<unk> 2 Any instance of<unk>  caused by a mutation not in SHD21A is categorized as<unk> 2, although the variation is typically caused by mutations in the<unk> IAP <unk> -linked inhibitor of apoptosis, also known as BIRC4) gene.<unk> 2 patients express different features from those typically found in<unk> 1 patients, such as splenomegaly and colitis. This variation is closely associated with HLH, so much so that some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of<unk> . Mutations in<unk> IAP inhibit the expression of the gene, which usually regulates the rate of lymphocyte apoptosis during an immune response. Nonfunctional<unk> IAP is unable to prevent lymphocytes from undergoing apoptosis in response to stimuli, which include the formation of the T-cell receptor (TCR)-CD3 complex, the binding the CD95 death receptor, and the activation TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). This leads to higher rates of lymphocyte apoptosis during a normal immune response.<unk> IAP-deficient individuals also produce low numbers of natural killer cells, a feature shared with<unk> 1 patients, which leads to a similarly inefficient response to EBV infection.
X-linked lymphoproliferative disease
Autoimmune lymphoproliferative syndrome
Adult-onset immunodeficiency syndrome
Primary immunodeficiency
RAS-associated autoimmune leukoproliferative disorder
X-linked severe combined immunodeficiency
Nodal marginal zone B cell lymphoma
Splenic marginal zone lymphoma