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)

The X-linked lymphoproliferative (XLP) syndrome is caused by mutations or deletions in the SH2D1A gene that encodes an SH2 domain protein named SH2D1A or SAP. The identification of a number of missense mutations within the protein's SH2 domain, each of which can directly cause disease, provides a unique opportunity to investigate the function of an interaction protein module, SH2, in the pathogenesis of XLP. We show here that SAP mutants found in XLP patients are defective in binding its physiological ligands signaling lymphocyte activating molecule (SLAM), a co-receptor in T cell activation, and Fyn, a Src family protein tyrosine kinase. Consequently, these mutants are deficient in signaling through the SLAM receptor. This is reflected by compromised abilities for the mutants to recruit Fyn to SLAM and to activate Fyn, by reduced phosphorylation of the receptor, and by deficiencies for the mutants in blocking binding of SHP-2 to SLAM. Furthermore, all mutants examined are defective in protein folding as manifested by their significantly reduced melting temperatures upon thermal denaturation, compared to that of SAP. Taken together, these results suggest that defects in ligand binding, receptor signaling, and protein folding collectively contribute to the loss of function for disease-causing SAP mutants.
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PMID:Disease-causing SAP mutants are defective in ligand binding and protein folding. 1467 64

The free Src homology 2 (SH2) domain protein SAP, encoded by the X-linked lymphoproliferative disease gene SH2D1A, controls signal transduction initiated by engagement of the SLAM-related receptors in T and NK cells. Here we demonstrate that SAP is required for phosphorylation of both SLAM and Ly9 in thymocytes and peripheral T cells. Furthermore, in vitro protein interaction studies and yeast two-hybrid analyses indicated that SAP binds directly to FynT and Lck. While SAP bound to both the SH3 domain and to the kinase domain of FynT, SAP bound solely to the kinase domain of Lck. The existence of a strong interaction between SAP and the SH3 domain of FynT prompted us to study the role of SAP in modulating the activity of FynT. In vitro addition of SAP to the autoinhibited form of FynT caused a large increase in FynT catalytic activity. By contrast, the SAP mutant R78E, which is unable to bind to the FynT SH3 domain, did not increase FynT activity and also displayed a reduced adaptor function upon transfection into T cells. Our results demonstrate that SAP is an adaptor that bridges SLAM and Ly9 with Src-like protein tyrosine kinases (PTKs), and has the ability to activate FynT.
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PMID:SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9. 1509 83

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

Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein-Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities including inverted CD4/CD8 and increased CD8(+) T-cell numbers. The number of IFN-gamma-producing T cells were markedly increased in the two patients studied so far. In addition, patient 2 showed mainly T cells, instead of B cells, to be infected with the EBV. Apart from an uncle of patient 3, who died of malignant lymphoma, family history was unremarkable in all cases. All three patients exhibited mutations in the SH2D1A gene, establishing the diagnosis of XLP. Protein expression was found on immunoblot analysis in one patient with a missense mutation. Development of persistent hypogammaglobulinemia after severe primary EBV infection seems to be a specific diagnostic sign for XLP even in males with unremarkable family history.
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PMID:Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease--report of three cases. 1535 10

The SH2D1A gene, which is altered or deleted in patients with X-linked lymphoproliferative disease, encodes the small protein SAP (for SLAM-associated protein) that is expressed in T and NK cells. A 22-bp fragment in close proximity to an initiator-like site was defined as the basal promoter of mouse SH2D1A, and a highly homologous 33-bp segment was defined as the human basal promoter. When an Ets consensus site was mutated, no reporter activity was detectable. Gel mobility supershift assays revealed that the two transcription factors Ets-1 and Ets-2 bind to the human and mouse sequences. The involvement of Ets-1 and Ets-2 in expression of SH2D1A was functionally confirmed by overexpression studies of their dominant-negative forms. We also found that SH2D1A mRNA decays very rapidly in mouse T cells, and its 3' untranslated region (UTR) has RNA-destabilizing activity in transfection studies with reporter/3' UTR constructs. As judged by RNA-gel mobility shift assays, this rapid degradation of SH2D1A mRNA was due to a balance in binding of the factors AUF1 and HuR to its 3' UTR. Although the SH2D1A mRNA level decreased upon triggering of the T cell receptor (TCR), the RNA degradation rate itself was not altered by TCR engagement.
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PMID:Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms. 1545 2

Mutations in the SH2D1A gene have been described in most patients with the clinical syndrome of X-linked lymphoproliferative disease (XLP). The diagnosis of XLP is still difficult given its clinical heterogeneity and the lack of a readily available rapid diagnostic laboratory test, particularly in patients without a family history of XLP. XLP should always be a consideration in males with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Four-color flow cytometric analysis was used to establish normal patterns of SH2D1A protein expression in lymphocyte subsets for healthy subjects. Three of 4 patients with XLP, as confirmed by the detection of mutations in the SH2D1A gene, had minimal intracellular SH2D1A protein in all cytotoxic cell types. The remaining patient lacked intracellular SH2D1A protein in CD56+ natural killer (NK) and T lymphocytes and had an abnormal bimodal pattern in CD8+ T cells. Carriers of SH2D1A mutations had decreased SH2D1A protein staining patterns compared with healthy controls. Eleven males with clinical syndromes consistent with XLP, predominantly EBV-HLH, had patterns of SH2D1A protein expression similar to those of healthy controls. Four-color flow cytometry provides diagnostic information that may speed the identification of this fatal disease, differentiating it from other causes of EBV-HLH.
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PMID:Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members. 1563 10

The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)-family receptors expressed on T and natural killer (NK) cells. In patients affected by X-linked lymphoproliferative (XLP) disease, mutations in the SH2D1A gene result in defective lytic activity. However, the mechanism by which SAP controls cytotoxic activity remains unclear. T-cell-receptor (TCR) activation of CD8(+) cytotoxic T cells (CTLs) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTLs from patients with XLP and hemophagocytic lymphohistiocytosis (HLH) display a specific lytic defect against autologous and allogeneic Epstein-Barr virus (EBV)-positive B cells. This defect is associated with the defective polarization of 2B4, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2B4 in normal CTLs reproduces the defects in lysis and polarization observed in SAP-deficient CTLs. Expression and regulation of the SLAM-family receptors SLAM, CD84, and 2B4, as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTLs. In addition, TCR stimulation leads to normal proliferation and production of interleukin 2 (IL-2), IL-4, and interferon-gamma (IFN-gamma). These results demonstrate that the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.
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PMID:SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. 1567 58

The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease. Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alphaGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alphaGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.
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PMID:Regulation of NKT cell development by SAP, the protein defective in XLP. 1574 36

X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule-associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4(+) T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4(+) T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4(+) T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.
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PMID:Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. 1576 93

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A(-/-) mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A(-/-) mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A(-/-) B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A(-/-) mice with CD4(+) T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naive SH2D1A(-/-) B cells became evident upon cotransfer with non-primed wt CD4(+) cells into Rag2(-/-) recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.
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PMID:Defective B cell responses in the absence of SH2D1A. 1577 82


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