Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations.
 ...
PMID:Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. 1147 68

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1A mutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP. (Blood. 2001;98:1268-1270)
 ...
PMID:SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses. 1149 83

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk or CD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in the XLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease.
 ...
PMID:Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. 1152 Jul 77

Common variable immunodeficiency (CVID) is the most frequently occurring primary immunodeficiency in both children and adults. The molecular basis of CVID has not been defined, and diagnosis involves exclusion of other molecularly defined disorders. X-linked lymphoproliferative disease (XLP) is a rare disorder in which severe immunodysregulatory phenomena typically follow Epstein-Barr virus (EBV) infection. Boys who survive initial EBV infection have a high incidence of severe complications, including progressive immunodeficiency, aplastic anaemia, lymphoproliferative disease and lymphoma. Survival beyond the second decade is unusual, although bone marrow transplantation can be curative. Until recently reliable diagnostic testing for XLP has not been available, but the identification of the XLP gene, known as SH2D1A, and coding for a protein known as SAP, means that molecular diagnosis is now possible, both by protein expression assays, and mutation detection, although the mutation detection rate in several series is only 55-60%. We describe three male patients initially diagnosed as affected by CVID, one of whom developed fatal complications suggestive of XLP, and all of whom lack expression of SAP. Two out of three have disease-causing mutations in the SAP gene, consistent with published data for XLP. These findings raise the possibility that a subgroup of patients with CVID may be phenotypic variants of XLP. Further studies are necessary to investigate this possibility, and also to clarify the prognostic significance of SAP abnormalities in such patients in the absence of typical features of XLP.
 ...
PMID:X-linked lymphoproliferative disease: three atypical cases. 1167 8

The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins. Mutations in SH2D1A cause the X-linked lymphoproliferative disease, a primary immunodeficiency. Here we report that a second gene encoding a free SH2 domain, EAT-2, is expressed in macrophages and B lympho cytes. The EAT-2 structure in complex with a phosphotyrosine peptide containing a sequence motif with Tyr281 of the cytoplasmic tail of CD150 is very similar to the structure of SH2D1A complexed with the same peptide. This explains the high affinity of EAT-2 for the pTyr motif in the cytoplasmic tail of CD150 but, unlike SH2D1A, EAT-2 does not bind to non-phosphorylated CD150. EAT-2 binds to the phosphorylated receptors CD84, CD150, CD229 and CD244, and acts as a natural inhibitor, which interferes with the recruitment of the tyrosine phosphatase SHP-2. We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells.
 ...
PMID:Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. 1168 25

The SH2 domain containing SH2D1A protein has been characterized in relation to the X-linked lymphoproliferative disease (XLP), a primary immunodeficiency that leads to serious clinical conditions after Epstein-Barr virus (EBV) infection. The SH2D1A gene is mutated in the majority of XLP patients. We previously detected SH2D1A in activated T and NK cells, but not in B lymphocytes. We have found SH2D1A protein in Burkitt lymphoma (BL) lines, but only in those that carried EBV and had a Group I (germinal center) phenotype. All the EBV-carrying Group III (immunoblastic) and the EBV-negative BL lines tested were SH2D1A-negative. Motivated by these differences, we studied the impact of EBV and the cellular phenotype on SH2D1A expression. We approached the former question with BL sublines after both the loss of the virus and subsequent reinfection. We also tested original EBV-negative BL lines carrying transfected EBV genes, such as EBNA1, EBNA2, EBNA6, EBER1, 2 and LMP1, respectively. In our experiments, no direct relationship could be seen between EBV and SH2D1A expression. We modified the phenotype of the Group I BL cells by LMP1 transfection or CD40 ligation. The phenotypic changes, indicated by expression of immunoblastic markers, e.g., SLAM, were accompanied by downregulation of SH2D1A. It seems, therefore, that the presence of EBV and the phenotype of the cell together regulate SH2D1A expression in the BL cells. It is possible that SH2D1A is expressed in a narrow window of B cell development represented by germinal center cells.
 ...
PMID:SH2D1A expression in Burkitt lymphoma cells is restricted to EBV positive group I lines and is downregulated in parallel with immunoblastic transformation. 1211 26

Mutations or deletions in the SH2D1A (src homology 2 domain protein 1A) gene result in a severe immunodeficiency called X-linked lymphoproliferative (XLP) disease. XLP is primarily characterized by a defective immune response against the Epstein-Barr virus (EBV), resulting in an unusually severe and often fatal clinical course following EBV infection. The second major cause of death is the development of B cell lymphomas, both in EBV-infected and EBV-negative patients. To study whether the clinical manifestation of XLP gene defects and/or polymorphisms extends beyond the classically recognized phenotype, we analyzed patients for the presence of SH2D1A gene alterations who presented with fatal or nonfatal, yet unusually severe or chronic EBV infections, and other possibly EBV-associated diseases, such as Hodgkin's lymphomas or nonendemic Burkitt's lymphomas and Burkitt-type leukemias. We identified mutations of the SH2D1A gene only in the majority of patients presenting with fatal mononucleosis or an XLP family history, but not in any of the other patients studied. The only alteration determined was a polymorphism in the 5' region of the SH2D1A gene both in patient groups as well as in controls.
 ...
PMID:Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma. 1222 1

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.
 ...
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.
 ...
PMID:Absence of SLAM mutations in EBV-associated lymphoproliferative disease patients. 1262 54

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.
 ...
PMID:[X-linked lymphoproliferative syndrome, EBV virus infection and defects in cytotoxicity lymphocyte regulation]. 1267 66


<< Previous 1 2 3 4 5 6 Next >>