Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, resulting in fatal infectious mononucleosis, dysgammaglobulinemia and malignant lymphoma. Recently, mutations in the SH2D1A gene, which encodes SLAM-associated protein (SAP), have been found to cause XLP. Although the molecular events behind XLP are largely unknown, there is evidence that affected males exhibited some immunohematological abnormalities, such as hypogammaglobulinemia or lymphoma, even prior to EBV infection. Because of the poor prognosis in XLP, an early diagnosis to patients and families is clinically of great importance. A glutathione-S-transferase-SAP fusion protein was used to immunize rats and generate mAb against human SAP to investigate its pathogenic role in XLP and develop a flow cytometric assay for detection of XLP. By flow cytometric and Western immunoblot analyses using an established anti-SAP mAb, termed KST-3, we determined that SAP was expressed intensely in thymocytes, but at lower levels in peripheral T cells and NK cells. In contrast, expression of SAP was negligible in B cells, monocytes or granulocytes. We found that SAP expression in T cells increased upon in vivo as well as in vitro activation. In two XLP survivors with SH2D1A mutations, a flow cytometric evaluation of activated T cells using KST-3 could demonstrate SAP deficiency as a diagnostic indicator of XLP. Through this approach, we identified three novel XLP families with SH2D1A mutations in Japan. A flow cytometric assessment of SAP expressed in activated T cells would lead to easy detection of XLP patients.
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PMID:Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection. 1235 86

X-linked lymphoproliferative disease is a rare inherited immunodeficiency in which affected males present abnormal responses to Epstein-Barr virus (EBV) infection. The gene defective in X-linked lymphoproliferative disease, SH2D1A (also named SAP or DSHP), has been identified and shown to code for an adapter protein that interacts with signaling lymphocytic activation molecule (SLAM) and several other members of the CD2 superfamily. SH2D1A is mutated in no more than 60% of X-linked lymphoproliferative disease patients. It could be postulated that a certain percentage of patients without apparent maternal transmission might be caused by other gene(s) in SH2D1A-related signal transduction pathways. Being a partner of SH2D1A and having a key role in proliferation and differentiation of the T- and B-lymphocytes, SLAM was considered as a candidate gene for patients who manifest symptoms of X-linked lymphoproliferative disease but who have no mutations in SH2D1A. As a first step, SLAM mutations were screened for from cDNA of the lymphoblastoid cell line of all available patients. Then conditions for PCR, single-strand conformational polymorphism (SSCP), heteroduplex analysis, and sequencing were established in all eight exons of SLAM. A total of 31 typical and atypical patients were analysed, from which six novel nucleotide variants were identified; however, none of these variants seems to cause abnormal function of the SLAM gene. Therefore, mutations in coding regions or splicing sites of SLAM are unlikely to play a major role in the mechanism of EBV-associated lymphoproliferation.
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PMID:Absence of SLAM mutations in EBV-associated lymphoproliferative disease patients. 1262 54

X-linked lymphoproliferative (XLP) disease is a human immune dysfunction characterized primarily by an inappropriate response to Epstein-Barr virus infection. In 1998, it was discovered that XLP is caused by inactivating mutations in the SAP/SH2D1A/DSHP gene. This gene codes for an immune cell-specific polypeptide termed SAP (SLAM-associated protein) that is composed almost exclusively of an Src homology 2 (SH2) domain. By way of its SH2 domain, SAP interacts with tyrosine-based motifs located in the cytoplasmic region of members of the SLAM (signaling lymphocyte activation molecule) family of receptors. Recent findings indicate that SAP is required for the function of SLAM-related receptors, as a consequence of its capacity to promote the recruitment and activation of the Src-related protein tyrosine kinase FynT, thereby allowing SLAM receptor-mediated protein tyrosine phosphorylation signals in immune cells. Functional and genetic analyses suggest that the phenotype associated with XLP is caused in large part by defects in the functions of SLAM-related receptors due to SAP deficiency.
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PMID:Molecular and immunological basis of X-linked lymphoproliferative disease. 1267 Apr 6

Mutations in SH2D1A, a gene that codifies for the regulatory protein SAP, result in uncontrolled activation of the SLAM (signaling lymphocyte-activation molecule) pathway. This X-linked immunodeficiency becomes evident when the patients are infected with Epstein Barr virus (EBV) and develop a fulminant form of infectious mononucleosis leading to a lymphoproliferative syndrome that is often fatal (X-linked lymphoproliferative syndrome, XLP). In those who survive, hypogammaglobulinemia and oncohematologic diseases are frequently observed. In this revision, the immuno-regulatory mechanisms involved in XLP immunopathology and the role of different effector cells (CD8 T lymphocytes, NK cells) are discussed.
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PMID:[X-linked lymphoproliferative syndrome, EBV virus infection and defects in cytotoxicity lymphocyte regulation]. 1267 66

X-linked lymphoproliferative disease is characterized by immune dysregulation and uncontrolled lymphoproliferation on exposure to Epstein-Barr virus (EBV). This disease has been attributed to mutations in the SAP gene (also denominated as SH2D1A or DSHP). To delineate the role of SAP in the pathophysiology of X-linked lymphoproliferative disease, a strain of sap-deficient mice has been generated by deleting exon 2 of the gene. After infection with murine gammaherpesvirus-68, which is homologous to EBV, the mutant mice exhibit more vigorous CD8+ T cell proliferation and more disseminated lymphocyte infiltration compared to their wild-type littermates. Chronic tissue damage and hemophagocytosis were evident in sap-deficient mice but not in their wild-type littermates. Concordantly, murine gammaherpesvirus-68 reactivation was observed in sap-deficient mice, indicating an impaired control of the virus. Notably, IgE deficiency and decreased serum IgG level were observed in mutant mice prior to and after murine gammaherpesvirus-68 infection, which reproduces hypo-gammaglobulinemia in X-linked lymphoproliferative disease patients. This mouse model will therefore be a useful tool for dissecting the various phenotypes of X-linked lymphoproliferative disease.
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PMID:Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia. 1296 53

Individuals with X-linked lymphoproliferative disease are susceptible to severe Epstein-Barr virus (EBV) infections that are often fatal. Mutations in signaling lymphocytic activation molecule-associated protein (SAP) are associated with this illness. We describe a patient with a novel serine-to-proline mutation at aa 57 in SAP and compare the location of the altered amino acid with all known missense mutations in the SAP-encoding SH2D1A gene, including those of 4 additional individuals whose cases have not been described elsewhere. The patient's genetic condition was discovered only after he exhibited an abnormal host response to primary EBV infection that resulted in hemophagocytic lymphohistiocytosis syndrome, which was complicated by marrow aplasia with terminal disseminated aspergillosis.
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PMID:Fatal hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection in a patient with a novel mutation in the signaling lymphocytic activation molecule-associated protein. 1458 85

The CD28 co-stimulatory pathway is well established for T cell activation; however, results from CD28 -/- mice suggest the existence of additional co-stimulatory pathways. Here we report the further characterization of a new member of the CD2 superfamily, NTB-A, important in T cell co-stimulation. NTB-A is expressed on T cells, and its expression is up-regulated on activated cells. Triggering of NTB-A with monoclonal antibodies in the absence of CD28 signals leads to T cell proliferation and interferon-gamma secretion but not interleukin-4. Cross-linking of NTB-A also induces phosphorylation of NTB-A and the association of SAP (SLAM-associated protein), the protein absent in X-linked lymphoproliferative disease. T helper cells differentiated by cross-linking NTB-A and CD3 developed predominantly into Th1 cells not Th2 cells. In vivo blocking of NTB-A interactions with its ligands by using soluble NTB-A-Fc fusion protein inhibits B cell isotype switching to IgG2a and IgG3, commonly induced by Th1-type cytokines. Most important, treatment of mice with NTB-A-Fc delays the onset of antigen-induced experimental allergic encephalomyelitis in myelin basic protein-T cell receptor transgenic mice, suggesting a role in T cell-mediated autoimmune disease. Regulation of interferon-gamma secretion, and not interleukin-4 in vitro, as well as inhibition of Th1 cell-induced isotype switching and attenuation of experimental allergic encephalomyelitis indicate that NTB-A is important for Th1 responses. The observation that cross-linking of NTB-A induces T cell activation, expansion, and Th1-type cytokine production suggests NTB-A is a novel co-stimulatory receptor. The identification of NTB-A as a regulator of T cell response paves the way to provide novel therapeutic approaches for modulation of the immune response.
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PMID:NTB-A, a new activating receptor in T cells that regulates autoimmune disease. 1498 14

The CD150 (SLAM) family consists of nine leukocyte cell-surface proteins involved in lymphocyte activation that belong to the immunoglobulin (Ig) superfamily. Six members of this family--CD84, CD150 (SLAM), CD229 (Ly9), CD244 (2B4), NTB-A, and CS1--associate with adapter proteins--SLAM-associated protein (SAP) and EAT-2. SAP is a short intracellular molecule that is mutated in humans with X-linked lymphoproliferative disease. Flow cytometric analysis of the expression of CD84, CD150, CD229, and CD244 cell-surface receptors on several leukocyte and lymphocyte subsets was performed. CD84 and CD150 were present on thymocytes, mature T cells and antigen-presenting cells. The expression of CD84 and CD150 was high on memory T cells. CD150 expression was strongly up-regulated after cell activation. In contrast to CD84, CD150 was absent on resting monocytes and immature dendritic cells (DCs). CD229 presented a pattern of expression restricted to lymphocytes. CD244 was preferentially expressed on natural killer cells, CD8(+) effector cells, resting monocytes, basophils, and eosinophils. We describe a broader distribution of CD84, CD150, CD229, and CD244 than previously reported and show that they are differentially expressed on hematopoietic cells. The heterogeneous expression of these receptors indicates that these molecules may play non-redundant functions in the regulation of both innate and adaptive immune responses.
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PMID:Differential expression of SAP and EAT-2-binding leukocyte cell-surface molecules CD84, CD150 (SLAM), CD229 (Ly9) and CD244 (2B4). 1524 68

The molecular basis of common variable immunodeficiency (CVID) is undefined, and diagnosis requires exclusion of other diseases including X-linked lymphoproliferative disease (XLP). This rare disorder of immunedysregulation presents typically after Epstein-Barr virus infection and results from defects in the SAP (SLAM associated protein) gene. SAP mutations have been found in a few patients diagnosed previously as CVID, suggesting that XLP may mimic CVID, but no large-scale analysis of CVID patients has been undertaken. We therefore analysed 60 male CVID and hypogammaglobulinaemic patients for abnormalities in SAP protein expression and for mutations in the SAP gene. In this study only one individual, who was found later to have an X-linked family history, was found to have a genomic mutation leading to abnormal SAP cDNA and protein expression. These results demonstrate that SAP defects are rarely observed in CVID patients. We suggest that routine screening of SAP may only be necessary in patients with other suggestive clinical features.
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PMID:Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency. 1532 Sep 10

The hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.
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PMID:Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. 1535 21


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