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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of early infancy. Mutations of the PRF1 gene have been identified in a subset of patients. However, the distinction between the different genetically determined and environmental subtypes of the disease remains a major issue to be solved. This may result in delayed or inappropriate application of bone marrow transplantation (BMT). We propose an algorithm that uses a combination of three rapid laboratory tests, i.e. perforin expression by peripheral lymphocytes, assessment of the behaviour of the 2B4 lymphocyte receptor and natural killer (NK) cell activity, to identify the different subgroups of HLH. In 19 patients diagnosed according to current criteria, we tested perforin expression, 2B4 receptor function and NK cell activity. PRF1 mutations were found in all seven patients showing absent perforin expression. In one male with abnormal behaviour of the 2B4 receptor, SH2D1A mutation confirmed the diagnosis of X-linked lymphoproliferative disease. Four patients with normal NK cell activity had evidence of associated infections. Of the seven with impaired NK cell activity, two had a probable genetically determined subtype of HLH and five appeared as sporadic, infection-associated cases. Improving the diagnostic approach may restrict the use of BMT, the only recognized curative treatment, to HLH patients with a documented poor prognosis while patients with milder disorders may be treated less intensively. Our flow chart could also lead to better selection of patients for specific gene analysis.
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PMID:Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. 1235 24

The X-linked lymphoproliferative (XLP) syndrome gene encodes a protein named SAP or SH2D1A that is composed of a single Src homology 2 (SH2) domain. Two models have been proposed for its function in lymphocyte signaling. One postulates that it acts as an inhibitor of interactions between the phosphatase SHP-2 and the immune receptor SLAM. The other suggests that it functions as an adaptor to promote the recruitment of a kinase, FynT, to SLAM. Here, we provide evidence in support of both roles for SAP. Using an array of peptides derived from the SLAM family of receptors, we demonstrate that SAP binds with comparable affinities to the same sites in these receptors as do the SH2 domains of SHP-2 and SHIP, suggesting that these three proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicate that SAP is capable of binding directly to FynT, an interaction mediated by the FynT SH3 domain. In cells, FynT was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was drastically enhanced by SAP. Because SAP also blocked the recruitment of SHP-2 to SLAM in these cells, we propose a dual functional role for SAP in SLAM signaling by acting both as an adaptor for FynT and an inhibitor to SHP-2 binding. The physiological relevance of the dual functional role for SAP is underscored by the observation that disease-causing SAP mutants exhibited significantly reduced affinities to both FynT and SLAM.
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PMID:Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors. 1245 14

SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome, a disease characterized by an inappropriate response to Epstein-Barr virus (EBV) infection. Through its SH2 domain, SAP associates with tyrosines in the cytoplasmic domain of the SLAM family of immune cell receptors, and is absolutely required for the function of these receptors. This property results from the ability of SAP to promote the selective recruitment and activation of FynT, a cytoplasmic Src-related protein tyrosine kinase (PTK). Here, we demonstrate that SAP operates in this pathway by binding to the SH3 domain of FynT, through a second region in the SAP SH2 domain distinct from the phosphotyrosine-binding motif. We demonstrate that this interaction is essential for SAP-mediated signalling in T cells, and for the capacity of SAP to modulate immune cell function. These observations characterize a biologically important signalling mechanism in which an adaptor molecule composed only of an SH2 domain links a receptor devoid of intrinsic catalytic activity to the kinase required for its function.
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PMID:Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. 1254 73

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

SH2D1A, the X-linked lymphoproliferative disease (XLP) gene, encodes a cytoplasmic protein that plays an essential role in controlling Epstein-Barr virus infection. It is expressed in T and NK cells, but not in B cells or in granulocytes. The promoter, the regulatory regions, as well as the mechanisms controlling its tissue-specific expression, are still unknown. We tested the hypothesis that DNA methylation might contribute to tissue-specific SH2D1A gene expression and analyzed the methylation status of 2,300 bp upstream of the ATG starting codon, the coding region and part of intron 1. By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, we show that a differential methylation pattern of CpG-rich regions in the 5' region and the adjacent exon 1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription.
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PMID:Differential methylation pattern of the X-linked lymphoproliferative (XLP) disease gene SH2D1A correlates with the cell lineage-specific transcription. 1270 35

Common variable immunodeficiency (CVID) is a highly heterogeneous disease with an unpredictable pattern. CVID appears to have an immunologic and clinical phenotype similar to some hereditary humoral immunodeficiencies, including X-linked lymphoproliferative disease (XLP). The differential diagnosis of CVID and XLP is clinically of importance, because the two diseases have markedly different prognoses and treatment. The recent identification of the XLP gene, known as SH2D1A, has permitted a definitive diagnosis of XLP. In this report, we describe a male patient with XLP who initially received a diagnosis of CVID and developed a fatal course. Using genetic analysis, we confirmed that the patient harbored the SH2D1A gene mutation. The results support the notion that the possibility of a SH2D1A gene mutation should be considered in hypogammaglobulinemic male patients before a diagnosis of CVID is made.
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PMID:Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency. 1289 50

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


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