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)

Mutations in the Bruton's tyrosine kinase (BTK) gene result in XLA. Despite the large numbers of BTK mutations reported, no correlation can be made between the clinical phenotype and the gene defects. Analysis of Btk protein expression and activity in individuals with XLA was performed to characterize the relationship between a particular mutation, the resultant Btk protein and the clinical phenotype. In most patients studied, including those with atypical phenotypes, there was complete absence of protein expression and activity. Furthermore, in two undiagnosed individuals with a clinical phenotype suggestive of XLA, lack of protein expression was used to confirm an abnormality in Btk. These results underline the importance of protein analysis prior to speculating on protein structure and function based on the gene mutation. Lack of Btk expression in atypical phenotypes suggests that there is redundancy in B lymphocyte signalling such that alternative signalling molecules, or mechanisms, can compensate for the lack of Btk. We also suggest that analysis of Btk expression can be used as an indicator of XLA. These rapid assays may be used to screen a wider spectrum of individuals with humoral immunodeficiency in order to characterize fully the extent of Btk deficiency.
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PMID:Bruton's tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA. 948

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.
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PMID:Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells. 952 24

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations of Bruton tyrosine kinase (Btk); Btk plays an essential role in the development of mature B cells. However, small numbers of B cells ("leaky B cells") are present in the peripheral blood of most XLA patients. In this study, we analyzed the function of these leaky B cells obtained from XLA patients. Enough numbers of B cells were available for analysis from five of nine XLA patients originally screened. Sequence analysis revealed missense mutations of Btk in four of the five XLA patients. No mutation was found in the coding region of Btk in one patient. Western blotting and/or flow cytometric analysis failed to detect Btk protein in all five patients. B cells isolated from peripheral blood of these XLA patients were CD5-, CD20+, CD19+, and CD21-. If stimulated with anti-CD40 and IL-4, XLA B cells proliferated normally and produced significant amounts of IgE. Anti-CD40 stimulation of XLA B cells resulted in normal expression of CD23. In addition, three of the five XLA patients studied were immunized with bacteriophage phiX174 and produced low but detectable levels of antiphage-specific Ab. Similarly, X-linked immunodeficiency mice, which carry a missense mutation in Btk, produced substantial amounts of antiphage Ab. These results indicate that CD40 signaling is intact in B cells lacking demonstrable Btk, and that leaky B cells in XLA patients can proliferate, undergo isotype switching, and differentiate into specific Ab-producing cells.
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PMID:Functional analysis of peripheral blood B cells in patients with X-linked agammaglobulinemia. 978 Jan 59

Mice with a targeted gene disruption of p85alpha, a regulatory subunit of phosphoinositide 3-kinase, had impaired B cell development at the pro-B cell stage, reduced numbers of mature B cells and peritoneal CD5+ Ly-1 B cells, reduced B cell proliferative responses, and no T cell-independent antibody production. These phenotypes are nearly identical to those of Btk-/- or xid (X-linked immunodeficiency) mice. These results provide evidence that p85alpha is functionally linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B cell development and functions.
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PMID:Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. 988 54

Pleckstrin homology (PH) domains have been shown to be involved in different interactions, including binding to inositol compounds, protein kinase C isoforms, and heterotrimeric G proteins. In some cases, the most important function of PH domains is transient localisation of proteins to membranes, where they can interact with their partners. Tec family protein tyrosine kinases contain a PH domain. In Btk, also PH domain mutations lead into an immunodeficiency, X-linked agammaglobulinemia (XLA). A new disease-causing mutation was identified in the PH domain. The structures for the PH domains of Bmx, Itk, and Tec were modelled based on Btk structure. The domains seem to have similar scaffolding and electrostatic polarisation but to have some differences in the binding regions. The models provide new insight into the specificity, function, and regulation of Tec family kinases.
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PMID:Pleckstrin homology domains of tec family protein kinases. 1054 6

Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder associated with abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and immunodeficiency. WAS is caused by a mutation in the gene encoding the cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet function is not established. WASp was recently shown to undergo tyrosine phosphorylation in platelets after activation by collagen, suggesting that it may play a selective role in activation by the adhesion molecule. In the present study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not to the integrin alpha2beta1. Tyrosine phosphorylation of WASp was blocked by Src family kinase inhibitors and reduced by treatment with wortmannin and in patients with X-linked agammaglobulinemia (XLA), a condition caused by a lack of functional expression of Btk. This indicates that Src kinases, phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the regulation of tyrosine phosphorylation of WASp. The functional importance of WASp was investigated in 2 WAS brothers who show no detectable expression of WASp. Platelet aggregation and secretion from dense granules induced by CRP and thrombin was slightly enhanced in the WAS platelets relative to controls. Furthermore, there was no apparent difference in morphology in WAS platelets after stimulation by these agonists. These observations suggest that WASp does not play a critical role in intracellular signaling downstream of tyrosine kinase-linked and G protein-coupled receptors in platelets.
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PMID:Regulation and function of WASp in platelets by the collagen receptor, glycoprotein VI. 1059 61

The Tec family is a recently emerging subfamily of non-receptor protein-tyrosine kinases (PTKs) represented by its first member, Tec. This family is composed of five members, namely Tec, Btk. Itk/Emt/Tsk, Bmx and Txk/Rlk. The most characteristic feature of this family is the presence of a pleckstrin homology (PH) domain in their protein structure. The PH domain is known to bind phosphoinositides; on this basis, Tec family PTKs may act as merge points of phosphotyrosine-mediated and phospholipid-mediated signaling systems. Many Tec family proteins are abundantly expressed in hematopoietic tissues, and are presumed to play important roles in the growth and differentiation processes of blood cells. Supporting this, mutations in the Btk gene cause X chromosome-linked agammaglobulinemia (XLA) in humans and X chromosome-linked immunodeficiency (Xid) in mice, indicating that Btk activity is indispensable for B-cell ontogeny. In addition, Tec family kinases have been shown to be involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein-coupled receptors and integrin molecules. Efforts are being made to identify molecules which interact with Tec kinases to transfer Tec-mediated signals in vivo. Candidates for such second messengers include PLC-gamma2, guanine nucleotide exchange factors for RhoA and TFII-I/BAP-135. This review summarizes current knowledge concerning the input and output factors affecting the Tec kinases.
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PMID:Tec family of protein-tyrosine kinases: an overview of their structure and function. 1064 81

The role of phosphatidylinositol 3,4,5-trisphosphate (PI3,4,5P(3)) and Btk in signalling by the collagen receptor glycoprotein VI was investigated. PI3,4,5P(3) was increased in platelets from mice deficient in the SH2 domain-containing inositol 5-phosphatase (SHIP), in response to collagen related peptide (CRP). Tyrosine phosphorylation and activation of phospholipase Cgamma2 (PLCgamma2) were unaltered in SHIP(-/-) platelets, whereas Btk was heavily tyrosine phosphorylated under basal conditions and maximally phosphorylated by low concentrations of CRP. There was an increase in basal Ca(2+), maximal expression of P-selectin, and potentiation of Ca(2+) and aminophospholipid exposure to CRP in SHIP(-/-) platelets in the presence of Ca(2+) (1 mM). Microinjection of PI3,4, 5P(3) into megakaryocytes caused a 3-fold increase in Ca(2+) in response to CRP, which was absent in X-linked immunodeficiency (Xid) mice, which have a mutation in the PH domain of Btk. There was a corresponding partial reduction in the sustained level of intracellular Ca(2+) in response to CRP in Xid mice but no change in PLC activity. These results demonstrate a novel pathway of Ca(2+) entry that involves PI3,4,5P(3) and Btk, and which is independent of increased PLC activity.
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PMID:Phosphatidylinositol 3,4,5-trisphosphate regulates Ca(2+) entry via btk in platelets and megakaryocytes without increasing phospholipase C activity. 1085 25

Several immunodeficiency-related genes have been identified and a large number of mutations in these genes. Currently, a genetic defect has been determined in more than 2000 patients. Only recently has it become possible to address structure-function effects of these mutations in the corresponding proteins. The consequences of mutations in structure are discussed for Btk in X-linked agammaglobulinemia (XLA), Jak3 in T-B+ severe combined immunodeficiency (SCID), p47phox and p67phox in autosomal chronic granulomatous disease (CGD) and SH2D1 A in X-linked lymphoproliferatine disease (XLP). The experimental and homology modelling derived structures were used to analyze mechanisms related to these diseases.
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PMID:Structure-function effects in primary immunodeficiencies. 1097 97

X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency disorder that is caused by a differentiation block leading to almost complete absence of B lymphocytes and plasma cells. The affected protein is a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase (Btk). Btk along with Tec, Itk, Bmx and Txk belong to a distinct family of protein kinases. These proteins contain five regions; PH, TH, SH3, SH2 and kinase domains. Mutations causing XLA may affect any of these domains. About 380 unique mutations have been identified and are collected in a mutation database, BTKbase. Here, we describe the structure, function, and interactions of the affected signaling molecules in atomic detail.
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PMID:Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). 1110 16


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