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

The gene defect responsible for X-linked lymphoproliferative syndrome, SH2D1A (SH2-domain-containing gene 1A), was recently cloned. This gene encodes a small protein of 128 amino acids containing a single SH2 domain, which is thought to play an important role in signal transduction in activated T cells. The definition of SH2D1A protein function will provide insight into the pathogenesis of fatal Epstein-Barr virus infection, lymphomas, Hodgkins disease, immunodeficiency, aplastic anemia and lymphohistiocytic disorders that characterize the syndrome.
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PMID:The abnormal gene in X-linked lymphoproliferative syndrome. 1044 42

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency to Epstein-Barr virus (EBV). The gene responsible for XLP has recently been identified as the four-exon SH2D1A gene encoding a 128-amino-acid protein that contains an SH2-domain. Functional studies indicate the SH2D1A protein acts as a regulator of at least two signal transduction pathways initiated by the cell surface molecules SLAM and 2B4, respectively, and possibly related to the host immune response to EBV infection. We have carried out a systematic mutation study of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and have reconstructed the haplotypes of the patients. Four out of the 13 mutations detected are previously unreported. The identification of SH2D1A mutations in carriers from all three XLP families screened and the detection of mutations in two out of eight atypical patients indicates the usefulness of a DNA-based diagnosis for XLP disease.
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PMID:SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. 1059 19

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, involving primarily T and natural killer (NK) cells, which in the majority of cases exacerbates following exposure to Epstein-Barr virus (EBV). Prior to EBV infection, most boys with the defective XLP gene appear to be clinically healthy EBV infection in males with the defective XLP gene leads to three main phenotypes: severe and mostly fatal infectious mononucleosis (58%), lymphoproliferative disorders mostly of B-cell origin (30%) and/or dysgammaglobulinemia (31%). Later in life, dysgammaglobulinemia and malignant lymphoma may also develop in about 53% and 56% of EBV-negative XLP males, respectively This fact suggests that EBV may only act as a potent trigger of the earliest and most serious clinical phenotype of XLP, i.e. fatal infectious mononucleosis. XLP has an unfavorable prognosis. Successful transplanta tion of hematopoietic stem cells can cure this immunodeficiency In the future, gene therapy may eventually become an additional option to prevent XLP. The gene responsible for XLP, SH2-domain containing gene 1A (SH2D1A) has recently been identified and sequenced. SH2D1A encodes a polypeptide of 128 amino acids containing a single SH2 domain. Until now, 45 different SH2D1A gene mutations have been identified in patients with XLP SH2D1A is thought to play an important role in signal transduction in T and NK cells. In vitro, SH2D1A has been shown to interact as an adaptor protein with the signaling pathways through SLAM, a T-cell co-stimulatory molecule, and 2B4, an NK-cell-activating receptor. Further functional studies of the SH2D1A protein will probably provide new insights into the pathogenesis of severe infectious mononucleosis, malignant lymphomas and immunodeficiency in patients with XLP.
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PMID:X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein. 1121 3

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.
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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)
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PMID:SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses. 1149 83

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.
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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