Affinage

SH2D1A

SH2 domain-containing protein 1A · UniProt O60880

Length
128 aa
Mass
14.2 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH2D1A encodes SAP, a single-SH2-domain adaptor that transduces signaling from SLAM-family receptors and is the gene mutated in X-linked lymphoproliferative disease (XLP), where missense mutations disrupt either protein stability or receptor binding (PMID:10549287, PMID:11477068, PMID:16720617). Structurally, the SAP SH2 domain recognizes its targets through an unusual phosphotyrosine-independent 'three-pronged' mode, engaging both N-terminal and C-terminal residues flanking the tyrosine and binding phosphorylated and non-phosphorylated SLAM peptides with comparable affinity around a T/S-x-x-x-x-V/I consensus motif (PMID:10549287, PMID:10607564, PMID:11823424). SAP acts dually at SLAM-family receptors (SLAM/CD150, 2B4/CD244, NTB-A, CD84, CD229): it competitively displaces the inhibitory phosphatases SHP-2 and SHIP from the receptor cytoplasmic tail, and it uses a second surface on its SH2 domain to recruit the FynT kinase SH3 domain, driving receptor tyrosine phosphorylation and activating signaling (PMID:11313386, PMID:11489943, PMID:12458214, PMID:18951976). In the absence of SAP, these receptors default to inhibitory output, explaining the failure of XLP NK and CD8+ T cells to kill EBV-infected B cells and to respond to B-cell antigen presentation (PMID:11489943, PMID:22069374). Through SLAM signaling SAP is required for NKT cell development, T-dependent humoral immunity and germinal center formation, with both a T-cell and a B-cell-intrinsic requirement (PMID:15711562, PMID:15263031, PMID:15774582), and it controls cytokine balance and restrains CD8+ T-cell-driven immunopathology, in part by promoting restimulation-induced cell death (RICD) via inhibition of diacylglycerol kinase α and consequent diacylglycerol/Ras/PKCθ signaling at the immune synapse (PMID:11404475, PMID:26764158, PMID:16788096). SH2D1A expression is restricted to T and NK cells by lineage-specific promoter CpG demethylation, Ets-dependent transcription, and 3'UTR-mediated mRNA destabilization (PMID:15459902, PMID:12709835).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Structural studies answered how a single SH2 domain recognizes SLAM despite weak dependence on tyrosine phosphorylation, defining the unique 'three-pronged' binding mode that distinguishes SAP from canonical SH2 adaptors.

    Evidence X-ray crystallography and NMR of SAP–SLAM peptide complexes with phosphopeptide library screening and XLP mutation analysis

    PMID:10549287 PMID:10607564

    Open questions at the time
    • Did not establish the in vivo signaling consequence of phosphotyrosine-independent binding
    • Receptor partners beyond SLAM not structurally tested at this stage
  2. 2002 High

    A second NMR study generalized the three-pronged mechanism across distinct peptides and tied disease-causing mutants to specific binding defects, consolidating the structural basis for XLP pathogenicity.

    Evidence NMR of two SAP–peptide complexes, synthetic peptide screening, hydrogen exchange

    PMID:11823424

    Open questions at the time
    • SH2 domain flexibility not linked to a functional regulatory mechanism
  3. 2001 Medium

    Co-IP and mutagenesis on CD150 showed SAP acts as a switch between phosphatase partners, redirecting the receptor from SHP-2 to SHIP and thereby altering signaling output.

    Evidence Reciprocal co-immunoprecipitation and GST-fusion pulldown with tyrosine mutants in B cells

    PMID:11313386

    Open questions at the time
    • Single-lab data
    • Functional consequence of the SHIP/SHP-2 switch on cell behavior not directly measured here
  4. 2001 High

    Identification of NTB-A as a SAP-associated SLAM-family receptor demonstrated that loss of SAP converts an activating receptor to an inhibitory one, explaining the NK cytotoxicity defect against EBV-infected targets in XLP.

    Evidence Co-IP, mAb masking and cytotoxicity assays with XLP patient NK cells

    PMID:11489943

    Open questions at the time
    • Mechanism by which SAP loss flips receptor polarity not molecularly defined here
  5. 2002 High

    The dual-function model was established: SAP both blocks inhibitory phosphatases and actively recruits FynT to drive SLAM phosphorylation, unifying its competitive and adaptor roles.

    Evidence Peptide arrays, in vitro and cellular binding assays, co-IP and mutagenesis

    PMID:12458214

    Open questions at the time
    • Relative contribution of phosphatase exclusion vs FynT recruitment in vivo not quantified
  6. 2002 Medium

    SAP recruitment to 2B4 was shown to require PI3K activity, adding an upstream regulatory input to SAP-dependent NK signaling.

    Evidence Co-IP, pharmacological PI3K inhibition, NK cytotoxicity with patient cells

    PMID:11815622

    Open questions at the time
    • Single-lab finding
    • Molecular link between PI3K product and SAP recruitment unresolved
  7. 2001 High

    Systematic analysis of XLP mutations resolved two mechanistic classes—destabilizing versus binding-disrupting—providing a genotype-to-mechanism framework for the disease.

    Evidence Site-directed mutagenesis, protein half-life measurement, co-IP across SLAM/2B4/CD84/CD229

    PMID:11477068

    Open questions at the time
    • Did not connect each class to distinct clinical phenotypes
  8. 2001 High

    The first SAP knockout mouse showed normal lymphocyte development but dysregulated cytokine output (Th1 skewing, reduced IL-4/IgE) after infection, placing SAP downstream of T-cell activation in immune regulation.

    Evidence Sh2d1a-/- mice with LCMV/Toxoplasma challenge and cytokine measurement

    PMID:11404475

    Open questions at the time
    • Receptor-level mechanism linking SAP to cytokine balance not defined in this model
  9. 2004 High

    SAP was shown to be required for germinal center formation and T-dependent IgG responses, mechanistically explaining the humoral immunodeficiency of XLP and protection from a lupus model.

    Evidence KO mouse immunization, germinal center analysis, lupus/EAE models with T-independent controls

    PMID:15263031

    Open questions at the time
    • Did not assign the defect to a specific cell lineage
  10. 2005 High

    Adoptive cotransfer revealed a B-cell-intrinsic requirement for SAP in humoral responses, refining the view that SAP acts only in T cells.

    Evidence Cotransfer of SH2D1A-/- B cells with WT T cells into irradiated/Rag2-/- hosts

    PMID:15774582

    Open questions at the time
    • The B-cell SLAM-receptor circuit responsible was not molecularly identified
  11. 2005 High

    SAP was established as essential and cell-autonomous for NKT cell development, confirmed by bone marrow rescue in mice and skewed X-inactivation in human carriers.

    Evidence KO phenotyping, BM reconstitution, α-GalCer stimulation, X-inactivation analysis in XLP carriers

    PMID:15711562

    Open questions at the time
    • Developmental signaling step at which SAP acts in NKT lineage not pinpointed
  12. 2004 Medium

    Genetic epistasis in DT40 sublines separated SAP-dependent CD150-Akt signaling (Syk-dependent, SHIP-independent) from SAP-independent ERK signaling, mapping branch points downstream of the receptor.

    Evidence CD150 ligation in gene-deficient DT40 B-cell sublines with Akt/ERK phospho-readouts

    PMID:15315965

    Open questions at the time
    • Single-lab chicken cell system
    • Relevance to primary human B cells not confirmed
  13. 2000 Medium

    Early co-IP work proposed SAP partners beyond SLAM (Dok1) and an NF-κB activation activity, expanding candidate downstream pathways.

    Evidence Co-IP with phospho-Dok1, mutagenesis, NF-κB reporter with dominant-negative IKKβ

    PMID:10852966

    Open questions at the time
    • Single-lab data not integrated with the dominant SLAM-receptor model
    • NF-κB activity was SH2-domain-independent and physiological relevance unclear
  14. 2003 Medium

    Lineage-restricted expression of SH2D1A was tied to differential CpG methylation, providing an epigenetic basis for its T/NK-cell-specific function.

    Evidence Bisulfite sequencing and methylation-sensitive digestion across expressing vs non-expressing lineages

    PMID:12709835

    Open questions at the time
    • Causality of methylation vs transcription not established by perturbation
  15. 2004 Medium

    SH2D1A expression was shown to be jointly controlled by Ets-dependent transcription and AUF1/HuR-balanced mRNA stability, defining its regulatory logic.

    Evidence Reporter assays, gel supershift, dominant-negative Ets, RNA decay and RNA-gel shift assays

    PMID:15459902

    Open questions at the time
    • Single-lab data
    • Signals tuning AUF1/HuR balance in activated T cells unknown
  16. 2006 High

    CD8+ T-cell depletion in chronic LCMV infection demonstrated that SAP-deficient CD8+ T cells are the direct cause of XLP-like immunopathology, linking SAP loss to disease mechanism in vivo.

    Evidence SAP-KO chronic LCMV infection with CD8 depletion, germinal center and viral load readouts

    PMID:16788096

    Open questions at the time
    • Did not yet define the cell-intrinsic signaling lesion driving pathogenic CD8 expansion
  17. 2006 High

    The RICD pathway was defined: SAP normally inhibits DGKα to sustain diacylglycerol/Ras/PKCθ signaling and NUR77/NOR1-driven apoptosis, and DGKα inhibition rescues RICD and curbs CD8 immunopathology, providing a mechanistic and therapeutic axis.

    Evidence SAP-KO LCMV model and patient T cells, RICD and DAG signaling assays, pharmacological DGKα inhibition

    PMID:26764158

    Open questions at the time
    • Molecular link from SAP to DGKα inhibition not fully resolved
    • Translation to human therapy not established
  18. 2008 Medium

    SAP was shown to engage NCK1 as well as Fyn SH3 domains through the same SH2 surface and to support LAT/SLP-76 phosphorylation, broadening the kinase/adaptor network it nucleates at the TCR.

    Evidence NMR of SAP–SH3 interactions, siRNA knockdown, phospho-assays, T-cell proliferation

    PMID:18951976

    Open questions at the time
    • Single-lab data
    • Relative in vivo importance of NCK1 vs Fyn recruitment unclear
  19. 2011 High

    Human carrier mixed-chimerism experiments demonstrated SAP is specifically required for CD8+ T-cell responses to B-cell antigen presentation, and that NTB-A/2B4 acquire inhibitory function without SAP, explaining the selective EBV vulnerability of XLP.

    Evidence Female XLP carrier mixed cells, antigen-specific response assays, receptor blocking and ectopic NTB-A expression

    PMID:22069374

    Open questions at the time
    • Why B-cell APCs specifically depend on SAP signaling not fully resolved
  20. 2019 Medium

    Continued XLP mutation analysis (e.g. E17K, G16D) reinforced that selective loss of receptor binding with preserved protein stability is sufficient to cause disease, separating binding from stability defects.

    Evidence Mutant expression with quantitative binding assays to phosphorylated CD244 and SLAM/2B4

    PMID:15841490 PMID:16720617 PMID:31994322

    Open questions at the time
    • Genotype-phenotype severity correlations not established
    • In vivo signaling consequences of partial binding loss untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SAP biochemically inhibits DGKα and how SLAM-family receptors are reprogrammed from activating to inhibitory output in SAP's absence remain mechanistically unresolved.
  • No defined molecular intermediary between SAP and DGKα
  • Structural basis of inhibitory phosphatase default not determined
  • Isoform-based regulation (SAP-2) lacks functional in vivo evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 1
Partners
CD244DOK1FYNINPP5DNCK1PTPN11SLAMF1SLAMF6

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Crystal structures of SAP/SH2D1A reveal that its single SH2 domain binds both phosphorylated and non-phosphorylated SLAM peptides by engaging residues N-terminal to the tyrosine (in addition to C-terminal residues), defining a phosphotyrosine-independent, extended 'three-pronged' binding mode distinct from canonical SH2 domains. The consensus binding motif was identified as TIpYXX(V/I). XLP patient mutations that disrupt these extended interactions abolish SAP function. X-ray crystallography, phosphopeptide library screen, XLP mutation analysis Molecular cell High 10549287
1999 NMR studies of 15N/13C-labeled SAP complexed with SLAM peptides confirm that the SAP SH2 domain binds phosphorylated and non-phosphorylated SLAM peptides with comparable affinity (Kd ~150 nM pTyr, ~330 nM Tyr), recognizing both N-terminal and C-terminal sequences relative to the tyrosine residue ('three-pronged' mechanism). NMR spectroscopy, peptide binding affinity measurements Current biology High 10607564
2002 NMR structure of SAP/SH2D1A complexed with two distinct peptides confirms the 'three-pronged' binding mechanism; the SAP SH2 domain contains a consensus binding motif T/S-x-x-x-x-V/I lacking Tyr or pTyr, and disease-causing SAP mutants show binding defects that explain their pathogenicity. Hydrogen exchange studies reveal considerable flexibility in the SH2 domain. NMR spectroscopy, synthetic peptide screening, hydrogen exchange The EMBO journal High 11823424
2001 SAP/SH2D1A regulates the association of CD150 (SLAM) with either SHIP or SHP-2: in SH2D1A-expressing B cells CD150 coprecipitates with SH2D1A and SHIP, whereas in SH2D1A-negative cells CD150 associates only with SHP-2. GST-fusion pulldowns show that phosphorylated Y281 and Y327 in the CD150 cytoplasmic tail are essential for SHP-2 and SHIP binding, and SH2D1A facilitates SHIP recruitment to CD150, acting as a switch between these two phosphatases. Co-immunoprecipitation, GST-fusion pulldown with tyrosine mutants Journal of immunology Medium 11313386
2001 NTB-A, a novel SLAM-family glycoprotein on NK/T/B cells, undergoes tyrosine phosphorylation and associates with SAP/SH2D1A as well as SHP phosphatases. In XLP NK cells lacking SH2D1A, NTB-A mediates inhibitory rather than activating signals, contributing to the inability to kill EBV-infected B cells. Masking both NTB-A and 2B4 simultaneously maximally restores cytotoxicity in XLP-NK cells. Co-immunoprecipitation, mAb masking experiments, cytotoxicity assays with XLP patient NK cells The Journal of experimental medicine High 11489943
2002 SAP functions dually in SLAM signaling: (1) it competitively inhibits SHP-2 and SHIP binding to SLAM family receptors, and (2) it acts as an adaptor recruiting FynT kinase to SLAM via a direct interaction between the SAP SH2 domain surface and the FynT SH3 domain. FynT is required for SLAM tyrosine phosphorylation, which is dramatically enhanced by SAP. Disease-causing SAP mutants show reduced affinity for both FynT and SLAM. In vitro and in vivo binding assays, peptide array, cell transfection, co-immunoprecipitation, mutagenesis The Journal of biological chemistry High 12458214
2001 Analysis of 10 XLP missense mutations in SH2D1A reveals two mechanistic classes: (i) mutations causing markedly decreased protein half-life (Y7C, S28R, Q99P, P101L, V102G, X129R), and (ii) mutations causing structural changes that differentially affect binding to SLAM, 2B4, CD84, and CD229. Mutation T68I disrupts the hydrophobic cleft interaction with Val+3 of the binding motif, C42W disrupts the phosphotyrosine-binding pocket, and T53I specifically impairs non-phosphotyrosine interactions while preserving phosphorylated CD150 binding. In vitro binding assays, protein half-life measurement, site-directed mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 11477068
2001 SAP-deficient mice (Sh2d1a−/−) display normal lymphocyte development but, upon infection with LCMV or Toxoplasma gondii, show increased T cell activation, elevated IFN-γ production, reduced Ig-secreting cells, and decreased IL-4. Anti-CD3-stimulated splenocytes from uninfected SAP− mice produce increased IFN-γ and decreased IL-4 (Th1 skewing), with decreased serum IgE in vivo, indicating SAP controls cytokine balance downstream of T cell activation. Targeted gene knockout mouse model, cytokine measurement, infection challenge Proceedings of the National Academy of Sciences of the United States of America High 11404475
2005 SAP encoded by SH2D1A is essential for NKT cell development: Sh2d1a−/− mice completely lack NKT cells in thymus and periphery. The defect is hematopoietic cell-autonomous and can be rescued by reconstituting SAP expression in Sh2d1a−/− bone marrow. Seventeen XLP patients with germline SH2D1A mutations also lacked NKT cells, and female XLP carriers show completely skewed X-chromosome inactivation in NKT cells but not T or B cells. Knockout mouse phenotyping, bone marrow reconstitution, alpha-galactosylceramide stimulation, X-chromosome inactivation analysis in human carriers Nature medicine High 15711562
2004 SH2D1A is required for T-dependent humoral immune responses and germinal center formation. SH2D1A−/− mice are protected from experimental lupus (hypergammaglobulinemia, autoantibodies, renal disease) specifically because of defective germinal center formation and impaired T-dependent antigen-specific IgG responses, while T-independent responses remain normal. KO mouse model, immunization, germinal center analysis, autoimmune disease model (lupus), EAE model The Journal of experimental medicine High 15263031
2005 SH2D1A is required in both T cells and B cells for productive humoral immune responses. Adoptive cotransfer experiments show that SH2D1A−/− B cells are intrinsically defective in contributing to antigen-specific IgG production even when paired with wild-type CD4+ T cells, indicating a B cell-autonomous signaling role for SH2D1A. Germinal centers are absent in SH2D1A−/− mice after primary immunization. Adoptive cotransfer into irradiated or Rag2−/− hosts, immunization, germinal center analysis Proceedings of the National Academy of Sciences of the United States of America High 15774582
2002 SAP association with 2B4 (CD244) in NK cells requires PI3K activity: ligation of 2B4 leads to 2B4 phosphorylation, SAP recruitment, and association of PI3K p85 subunit. Pharmacological inhibition of PI3K (wortmannin or LY294002) prevents SAP recruitment to 2B4 without disrupting PI3K-p85 association with 2B4, and abolishes NK cytotoxicity in normal but not XLP NK cells. Co-immunoprecipitation, pharmacological inhibition, NK cytotoxicity assay with patient cells The Journal of biological chemistry Medium 11815622
2004 SH2D1A regulates CD150-mediated Akt signaling in B cells: using DT40 sublines deficient in specific signaling molecules, CD150-mediated Akt phosphorylation requires Syk and SH2D1A, is negatively regulated by Lyn and Btk, and is SHIP-independent. CD150-mediated ERK pathway activation requires SHIP but not SH2D1A. DT40 gene-deficient B cell sublines, CD150 ligation, Akt and ERK phosphorylation assays Blood Medium 15315965
2000 SH2D1A associates with Dok1 (p62dok) via its SH2 domain in a manner dependent on phosphorylation of Dok1 Y449 (in the sequence ALYSQVQK). An XLP-associated SH2 domain mutant fails to associate with Dok1. Overexpression of SH2D1A activates NF-κB in 293T cells via a pathway dependent on IκB kinase β but independent of the wild-type SH2 domain. Co-immunoprecipitation, site-directed mutagenesis, NF-κB reporter assay, dominant-negative kinase Proceedings of the National Academy of Sciences of the United States of America Medium 10852966
2008 SAP interacts with SH3 domains of Fyn and NCK1 via a surface on the SAP SH2 domain distinct from the phosphotyrosine-binding surface. NMR shows NCK1 and Fyn SH3 domains engage the same SAP residues with comparable affinities. SAP knockdown reduces NCK1 tyrosine phosphorylation and phosphorylation of downstream TCR signaling proteins LAT and SLP-76. SAP regulates T cell proliferation through ERK/MAP kinase. NMR analysis of SAP–SH3 interactions, siRNA knockdown, phosphorylation assays, T cell proliferation assay Cellular signalling Medium 18951976
2006 SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) due to diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased Ras and PKCθ signaling. Pharmacological inhibition of DGKα in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of pro-apoptotic proteins NUR77 and NOR1. DGKα inhibition prevents excessive CD8+ T cell expansion and IFN-γ production in SAP-deficient mice after LCMV infection. SAP-KO mouse LCMV infection model, RICD assay, diacylglycerol signaling measurements, pharmacological DGKα inhibition, NUR77/NOR1 induction Science translational medicine High 26764158
2011 SAP expression in CD8+ T cells is specifically required for their response to antigen presented by B cells but not other antigen-presenting cells. In female XLP carriers with mixed SAP+/SAP− cells, EBV-specific memory CD8+ T cells are exclusively SAP+, while CMV- and influenza-specific cells distribute equally. Blocking SLAM receptors NTB-A and 2B4 overcomes the inability of SAP− CD8+ T cells to respond to B cell antigen presentation; ectopic NTB-A expression on fibroblasts inhibits SAP− CD8+ T cell cytotoxicity, demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. Analysis of female XLP carrier cells (natural mixed chimerism), antigen-specific T cell response assays, receptor blocking antibodies, ectopic NTB-A expression on fibroblasts PLoS biology High 22069374
2004 SH2D1A gene expression is controlled by a combination of transcriptional and post-transcriptional mechanisms: a 22–33 bp basal promoter element containing an Ets consensus site is required for transcription, with Ets-1 and Ets-2 binding confirmed by gel mobility supershift and dominant-negative overexpression. SH2D1A mRNA decays rapidly in T cells, and its 3' UTR has RNA-destabilizing activity dependent on a balance between AUF1 and HuR binding. Reporter assays, gel mobility shift/supershift assays, dominant-negative Ets overexpression, RNA decay assays, RNA-gel mobility shift European journal of immunology Medium 15459902
2006 SAP deficiency causes profound germinal center defects and hypogammaglobulinemia during chronic LCMV infection in mice. Depletion of SAP-deficient CD8+ T cells blocks the immunopathology and clinical illness, providing the first direct demonstration that SAP-deficient CD8+ T cells are the primary cause of immunopathology in an XLP model. SAP-KO mouse chronic LCMV infection, CD8+ T cell depletion, germinal center analysis, viral load measurement Blood High 16788096
2003 Differential DNA methylation of CpG-rich regions in the 5' region and exon 1 of SH2D1A correlates with cell lineage-specific transcription: T and NK cells (which express SH2D1A) show hypomethylation, while B cells and granulocytes (which do not express it) show hypermethylation. Bisulfite sequencing, methylation-sensitive restriction enzyme digestion Immunogenetics Medium 12709835
2006 Four XLP missense mutations (Y54C, I84T, F87S) and a frameshift insertion (fs82→X103) each dramatically reduce SAP protein half-life. The I84T mutation does not prevent SAP binding to SLAM, CD84, or 2B4 but reduces downstream SLAM signaling, demonstrating that impaired signal transduction can be mechanistically separable from impaired receptor binding. Protein half-life measurement, co-immunoprecipitation binding assays, downstream signaling assays in primary lymphocytes and transfected cell lines International immunology Medium 16720617
2005 A new XLP disease-causing SAP missense mutation (p.G16D) results in a protein with normal half-life but defective binding to SLAM and 2B4 ligands, as demonstrated by expressing the mutant cDNA in COS cells and testing binding to physiological ligands. Site-directed mutagenesis, COS cell expression, co-immunoprecipitation binding assay Human mutation Medium 15841490
2013 A new murine SAP isoform (SAP-2) arising from a cryptic exon contains 18 additional amino acids inserted into the phosphotyrosine-binding structural region of the SH2 domain. Functional analysis in vitro shows SAP-2 is non-functional due to decreased protein stability, suggesting cells could modulate SAP-mediated activity by regulating isoform ratios. RT-PCR isoform identification, protein stability assay, in vitro functional analysis Science China. Life sciences Low 24369347
2019 A novel SH2D1A variant (c.49G>A, p.E17K) results in a SAP protein with normal expression levels but >95% reduction in binding to phosphorylated CD244 (2B4), demonstrating that loss of receptor binding, rather than protein instability, can be the sole mechanistic defect in some XLP mutations. Flow cytometry (SAP protein expression), biochemical binding assay to phosphorylated CD244 Pediatric blood & cancer Medium 31994322

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Regulation of NKT cell development by SAP, the protein defective in XLP. Nature medicine 302 15711562
2010 Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 266 21119115
2001 NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. The Journal of experimental medicine 257 11489943
2010 X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 220 20926771
2001 Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proceedings of the National Academy of Sciences of the United States of America 212 11404475
1999 Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Molecular cell 202 10549287
2000 Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 190 11049992
2001 CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. Journal of immunology (Baltimore, Md. : 1950) 170 11313386
2007 The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells. The EMBO journal 166 17853891
1982 Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): update on studies of the registry. The American journal of medicine 160 6283885
2001 Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 118 11159547
2006 Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes. Proceedings of the National Academy of Sciences of the United States of America 117 16966603
2022 Global genetic diversity status and trends: towards a suite of Essential Biodiversity Variables (EBVs) for genetic composition. Biological reviews of the Cambridge Philosophical Society 113 35415952
2011 Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLoS biology 99 22069374
2014 XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. Journal of clinical immunology 98 25085526
1999 Novel mode of ligand binding by the SH2 domain of the human XLP disease gene product SAP/SH2D1A. Current biology : CB 94 10607564
2001 Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Blood 93 11520777
2004 SH2D1A regulates T-dependent humoral autoimmunity. The Journal of experimental medicine 85 15263031
2017 Building essential biodiversity variables (EBVs) of species distribution and abundance at a global scale. Biological reviews of the Cambridge Philosophical Society 83 28766908
2002 A "three-pronged" binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome. The EMBO journal 80 11823424
1999 Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Human molecular genetics 76 10556288
2001 Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. The Journal of biological chemistry 71 11477068
2002 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. The Journal of biological chemistry 70 12458214
2005 Defective B cell responses in the absence of SH2D1A. Proceedings of the National Academy of Sciences of the United States of America 56 15774582
2005 Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members. Blood 50 15632210
1996 Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone marrow transplantation 49 8733691
2000 The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B. Proceedings of the National Academy of Sciences of the United States of America 46 10852966
2016 Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1. Science translational medicine 45 26764158
2003 Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection. Blood 44 14604960
2001 SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses. Blood 43 11493483
1990 Partial Xq25 deletion in a family with the X-linked lymphoproliferative disease (XLP). Cancer genetics and cytogenetics 40 1972651
2018 Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. Clinical genetics 39 29665027
2011 Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 38 21674762
2006 Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease. Blood 38 16788096
2002 Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase. The Journal of biological chemistry 35 11815622
2009 Proof for EBV's sustaining role in Burkitt's lymphomas. Seminars in cancer biology 33 19628040
2004 The adaptor protein SH2D1A regulates signaling through CD150 (SLAM) in B cells. Blood 31 15315965
1999 SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. Human genetics 31 10598819
2008 The XLP syndrome protein SAP interacts with SH3 proteins to regulate T cell signaling and proliferation. Cellular signalling 30 18951976
2002 A spectrum of mutations in SH2D1A that causes X-linked lymphoproliferative disease and other Epstein-Barr virus-associated illnesses. Leukemia & lymphoma 30 12152986
2002 SH2D1A expression in Burkitt lymphoma cells is restricted to EBV positive group I lines and is downregulated in parallel with immunoblastic transformation. International journal of cancer 27 12115526
2018 Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening. European journal of medicinal chemistry 26 30611057
2014 Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients with SH2D1A and XIAP/BIRC4 mutations. Cytometry. Part B, Clinical cytometry 26 24616127
2002 Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency. European journal of pediatrics 26 12447665
2015 Epstein-Barr Viruses (EBVs) Deficient in EBV-Encoded RNAs Have Higher Levels of Latent Membrane Protein 2 RNA Expression in Lymphoblastoid Cell Lines and Efficiently Establish Persistent Infections in Humanized Mice. Journal of virology 24 26339045
2009 Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP). Cellular immunology 23 19595300
2003 Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency. International journal of hematology 23 12894850
2014 Clinical Flow Cytometric Screening of SAP and XIAP Expression Accurately Identifies Patients with SH2D1A and XIAP/BIRC4 Mutations. Cytometry. Part B, Clinical cytometry 22 26305518
2003 Expression of SH2D1A in five classical Hodgkin's disease-derived cell lines. International journal of cancer 22 12594824
2013 Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms. Pediatric blood & cancer 21 23589280
2008 X-linked lymphoproliferative disease (XLP): a model of impaired anti-viral, anti-tumor and humoral immune responses. Immunologic research 21 18815745
2022 Genome Editing With TALEN, CRISPR-Cas9 and CRISPR-Cas12a in Combination With AAV6 Homology Donor Restores T Cell Function for XLP. Frontiers in genome editing 19 35677600
2019 Systemic Epstein-Barr Virus-Positive T/NK Lymphoproliferative Diseases With SH2D1A/XIAP Hypomorphic Gene Variants. Frontiers in pediatrics 19 31231620
2000 Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease. Biochemical and biophysical research communications 19 10694488
1998 Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP). Bone marrow transplantation 19 9758353
1997 A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus. Genomics 19 9027486
1993 High-resolution mapping of probes near the X-linked lymphoproliferative disease (XLP) locus. Genomics 18 8406447
2015 Complete genome sequence of vB_DshP-R2C, a N4-like lytic roseophage. Marine genomics 17 25795023
2017 Dissecting the regulation of EBV's BART miRNAs in carcinomas. Virology 15 28259048
2011 Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry. Cytometry. Part B, Clinical cytometry 15 20632414
2005 Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease. Human mutation 15 15841490
2004 Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms. European journal of immunology 14 15459902
2006 Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP. International immunology 13 16720617
2002 Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma. Annals of hematology 13 12224001
2001 No mutations of SAP/SH2D1A/DSHP and perforin genes in patients with Epstein-Barr virus-associated hemophagocytic syndrome in Japan. Journal of medical virology 13 11536244
2023 Overexpression of SH2D1A promotes cancer progression and is associated with immune cell infiltration in hepatocellular carcinoma via bioinformatics and in vitro study. BMC cancer 12 37858067
2012 HHV-8-related hemophagocytic lymphohistiocytosis in a boy with XLP phenotype. Journal of pediatric hematology/oncology 11 22258354
2019 Rare cause of Hemophagocytic Lymphohistiocytosis due to mutation in PRF1 and SH2D1A genes in two children - a case report with a review. BMC pediatrics 10 30849948
2018 Management of XLP-1 and ITK deficiency: The challenges posed by PID with an unpredictable spectrum of disease manifestations. Clinical immunology (Orlando, Fla.) 10 30572125
2002 SH2D1A expression reflects activation of T and NK cells in cord blood lymphocytes infected with EBV and treated with the immunomodulator PSK. Immunology letters 10 11803050
2013 Association of a single nucleotide polymorphism in the SH2D1A intronic region with systemic lupus erythematosus. Lupus 9 23554038
2012 Skin lesions in a boy with X-linked lymphoproliferative disorder: comparison of 5 SH2D1A deletion cases. Pediatrics 9 22271700
2005 The role of CD150-SH2D1A association in CD150 signaling in Hodgkin's lymphoma cell lines. Experimental oncology 9 15812353
1998 A new candidate region for the positional cloning of the XLP gene. European journal of human genetics : EJHG 9 9801876
2011 CD4+ T Lymphocytes with follicular helper phenotype (T(FH)) in patients with SH2D1A deficiency (XLP). Clinical immunology (Orlando, Fla.) 8 21996454
2003 Differential methylation pattern of the X-linked lymphoproliferative (XLP) disease gene SH2D1A correlates with the cell lineage-specific transcription. Immunogenetics 8 12709835
2020 Diagnostic challenges for a novel SH2D1A mutation associated with X-linked lymphoproliferative disease. Pediatric blood & cancer 6 31994322
2017 Novel Mutations in SH2D1A Gene in X-linked Lymphoproliferative Syndrome, Diagnosed After B-Cell Non-Hodgkin Lymphoma. Journal of pediatric hematology/oncology 6 28267077
2015 Study of SH2D1A gene mutation in paediatric patients with B-cell lymphoma. Allergologia et immunopathologia 6 25982576
2014 The value of DNA storage and pedigree analysis in rare diseases: a 17-year-old boy with X-linked lymphoproliferative disease (XLP) caused by a de novo SH2D1A mutation. European journal of pediatrics 6 24723092
2007 Factors involved in the generation of memory CD8+ T cells in patients with X-linked lymphoproliferative disease (XLP). Clinical and experimental immunology 6 17302894
1993 Evaluation of families wherein a single male manifests a phenotype of X-linked lymphoproliferative disease (XLP). American journal of medical genetics 6 8256804
2019 Fatal Central Nervous System Lymphocytic Vasculitis after Treatment for Burkitt Lymphoma in a Patient with a SH2D1A Mutation. The Pediatric infectious disease journal 5 30138256
2017 Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing. PloS one 5 28231257
2015 Maternal onset de novo SH2D1A mutation and lymphocytic choriomeningitis virus infection in a patient with X‑linked lymphoproliferative disease type 1: a case report. Molecular medicine reports 5 25572984
2012 The -346T polymorphism of the SH2D1A gene is a risk factor for development of autoimmunity/lymphoproliferation in males with defective Fas function. Human immunology 5 22425739
2012 Fatal EBV infection and variable clinical manifestations in an XLP-1 pedigree - rapid diagnosis of primary immunodeficiencies may save lives. Klinische Padiatrie 5 23143765
2011 X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis. Case reports in medicine 5 21541208
1986 Epstein-Barr virus (EBV) and X-linked lymphoproliferative syndrome (XLP). AIDS research 5 3030340
2022 Exon skipping caused by a complex structural variation in SH2D1A resulted in X-linked lymphoproliferative syndrome type 1. Molecular genetics & genomic medicine 4 35092357
2022 Potential pathogenic mechanism of type 1 X-linked lymphoproliferative syndrome caused by a mutation of SH2D1A gene in an infant: A case report. Medicine 4 36254040
2021 Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation. Frontiers in immunology 4 34987501
2018 Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report. BMC medical genetics 4 29649976
2017 Characterization of a novel disease-causing mutation in exon 1 of SH2D1A gene through amplicon sequencing: a case report on HLH. BMC medical genetics 4 28196537
2012 Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia. Clinical immunology (Orlando, Fla.) 4 23280491
2009 Increased lymphocyte viability after non-stimulated peripheral blood mononuclear cell (PBMC) culture in patients with X-linked lymphoproliferative disease (XLP). Clinical immunology (Orlando, Fla.) 4 19576857
2025 Fatal HLH in patients with X-linked lymphoproliferative disease 1 due to a novel variant in SH2D1A: case report. Frontiers in immunology 3 40458416
2022 Patients with XLP type 1 have variable numbers of NKT cells. British journal of haematology 3 35355252
2013 Identification of a new isoform of the murine Sh2d1a gene and its functional implications. Science China. Life sciences 3 24369347
2008 Sequence analysis of the SRGN, AP3B1, ARF6, and SH2D1A genes in familial hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 3 18000860

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