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)

Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase critical for B cell development and function. Mutations in BTK result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Using a random mutagenesis scheme, we isolated a gain-of-function mutant called BTK* whose expression drives growth of NIH 3T3 cells in soft agar. BTK* results from a single point mutation in the pleckstrin homology (PH) domain, where a Glu is replaced by Lys at residue 41. BTK* shows an increase in phosphorylation on tyrosine residues and an increase in membrane targeting. Transforming activity requires kinase activity, a putative autophosphorylation site, and a functional PH domain. Mutation of the SH2 or SH3 domains did not affect the activity of BTK*. Expression of BTK* could also relieve IL-5 dependence of a B lineage cell line. These results show that transformation activation and regulation of BTK are critically dependent on the PH domain.
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PMID:Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. 753 39

Bruton's tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X-linked agammaglobulinemia (XLA) and has been described as a new member of Src-related cytoplasmic protein tyrosine kinases. We have recently characterized the structure of the entire gene encoding Btk and developed a polymerase chain reaction (PCR)-based assay to detect germline mutations within it. In this report we describe six mutations, five of which are novel, of the Btk gene in patients with XLA and demonstrate the inheritance pattern of the defect within the families of the affected individuals. The mutations found include two nonsense and two missense mutations, a single base deletion at an intron acceptor splice site, and a 16-bp insertion. A single strand conformation polymorphism was also found in the 5' end of intron 8 with the same assay. This technique has provided a powerful tool for direct analysis of the Btk gene for the diagnosis of XLA and carrier detection. The identification of new mutations may eventually reveal the role of Btk in the signaling pathways involved in B-cell development.
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PMID:Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia. 762 83

X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinase, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 120-kD protein present in human B cells as being bound by the SH3 domain of Btk and which, after B cell receptor stimulation, is one of the major substrates of tyrosine phosphorylation. We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120cbl provides evidence for an analogous role for p120cbl in B cell signaling pathways. The p120cbl protein is the first identified ligand of the Btk SH3 domain.
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PMID:The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase. 762 18

To investigate the role of B cells in the development of experimental Staphylococcus aureus-induced arthritis, we used X-linked immunodeficiency (xid) mice that carry a Bruton's tyrosine kinase mutation affecting the function of B cells. NFR/N.xid and congenic NFR/N mice were inoculated i.v. with a toxic syndrome toxin-1 producing S. aureus LS-1 strain. B cell-deficient NFR/N.xid mice developed less frequent (p < 0.01) and less severe (p < 0.01) arthritis than NFR/N mice did. These clinical findings were corroborated by histopathologic evaluation, indicating that NFR/N.xid mice had significantly lower (p < 0.01) erosivity of the disease. Interestingly, infected NFR/N.xid mice showed decreased bacterial burden in blood, joints, and other organs compared with the control mice. Serologic studies displayed poor B cell responses to staphylococcal cell walls, toxic shock syndrome toxin-1, and ssDNA, accompanied by a low level of Igs in infected NFR/N.xid mice. More importantly, xid defect affected cytokine profile. The in vitro experiments showed that the lymphocytes from NFR/N.xid mice had low IL-6, but high IFN-gamma production upon stimulation with staphylococcal cell walls compared with NFR/N mice. Furthermore, the in situ hybridization technique revealed the relative increase of IFN-gamma, but marked decrease of IL-1 beta mRNA expression in spleens of infected NFR/N.xid mice. No significant difference in IL-4, IL-10, and TNF-alpha mRNA expression was found between both strains. Our findings demonstrate that B cells may, directly or indirectly, contribute to the pathogenesis of septic arthritis. The results indicate that increased IFN-gamma production along with low IL-6 and IL-1 beta synthesis found in xid mice may provide a more favorable outcome of S. aureus arthritis.
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PMID:Mice with the xid B cell defect are less susceptible to developing Staphylococcus aureus-induced arthritis. 763 57

X-linked agammaglobulinemia is a primary inherited immunodeficiency resulting in a lack of or dramatic reduction in the number of mature B lymphocytes and, thus, greatly reduced levels of serum immunoglobulin. The defect results from mutations in the gene for Bruton's tyrosine kinase (Btk). Using rabbit antisera generated against Btk, we have demonstrated an increase in the level of in vitro kinase activity present in anti-Btk immunoprecipitates from B cells following stimulation with anti-immunoglobulin antibody. This increase in immune complex kinase activity is detectable 1 to 2 min following stimulation and remains elevated for over 30 min. A similar increase was not seen with two late pre-B cell lines investigated in the same way. This stimulation of activity may suggest a role for Btk in signalling through the B cell receptor or associated proteins, in mature B cells.
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PMID:The protein defective in X-linked agammaglobulinemia, Bruton's tyrosine kinase, shows increased autophosphorylation activity in vitro when isolated from cells in which the B cell receptor has been cross-linked. 773 82

Synovial fluid from patients with rheumatoid arthritis (RA-SF) contains in vivo produced cytokines and inflammatory mediators, including a factor that induces IgG2b production of lipopolysaccharide (LPS) preactivated murine B lymphocytes. In order to determine the mechanism by which RA-SF acts on LPS activated mouse B cells, CBA/N mice were used as an experimental model. The X-linked immunodeficiency of these mice is caused by a point mutation in the Bruton's tyrosine kinase (btk) gene. We have earlier shown that RA-SF can reconstitute the CBA/N B cell deficiency in vitro and in vivo, with regard to IgG2b production after LPS stimulation. Since transforming growth factor (TGF)-beta has been suggested to be a switch factor for IgG2b, we aimed at investigating the role of TGF-beta in our experimental system. We found that TGF-beta could not mimic the effect of RA-SF on CBA spleen cells. A small increase of IgG2b secretion was observed with spleen cells from normal CBA mice, whereas Ig secretion of all isotypes was suppressed in CBA/N spleen cells treated with TGF-beta at any concentration. Neutralizing antibodies against TGF-beta suppressed the response of CBA B cells, whereas the response by CBA/N B cells was enhanced by the same antibody preparation. Here we also show that the abnormal B cell responsiveness to TGF-beta, typical of CBA/N, co-segregates with the btk mutation in male (CBA x CBA/N)F2 spleen cells. This was determined by allele specific PCR recognizing the identified base substitutions of the btk gene, typical of the two strains. We propose that RA-SF contains a factor, separate from TGF-beta, that is involved in the differentiation of IgG2b expressing cells.
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PMID:Differential sensitivity to transforming growth factor (TGF)-beta of CBA and of CBA/N B cells demonstrates that the IgG2b inducing factor in synovial fluid from rheumatoid arthritis patients is not identical to TGF-beta. 779 24

The defective gene responsible for the recessively inherited immunodeficiency X-linked agammaglobulinemia (XLA) has been shown to encode a cytoplasmic protein tyrosine kinase of the Src family designated Btk (Bruton's tyrosine kinase). To facilitate the search for germline mutations of the Btk gene, we have characterized its genomic structure. Eighteen introns were positioned within the approximately 37 kb gene. Each of the exon/intron boundaries were defined and sequenced, and all but two conform to consensus sequences. We have utilized the genomic organization of Btk and the intervening sequence data to design an assay for amplifying each of the 19 exons from XLA patient DNA for single strand conformation polymorphism (SSCP) analysis. By using this method we have identified mutations in 12 of 14 unrelated affected males: seven different base substitutions and two small deletions. Two of the mutations described in exon 15 of the kinase domain were found in more than one patient and may represent a mutation hot spot. Exon scanning has proven to be a valuable method for identifying the patient mutations in genomic DNA without the use of cDNA. The mutations are easily confirmed with direct sequencing of the amplified exons. This approach will greatly benefit XLA family studies involving carrier detection and prenatal diagnosis. In addition, the mutations identified may reveal residues involved in the specific protein interactions necessary in the B-cell developmental pathway, of which Btk is an integral component.
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PMID:Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. 788 Mar 20

X-linked agammaglobulinemia (XLA) is an inherited human immunodeficiency disease, characterized by an arrest in B-cell development, which results in a dramatic decrease in immunoglobulin production. The gene product defective in XLA has been identified as a cytoplasmic protein tyrosine kinase, named Bruton's tyrosine kinase (Btk). The dramatic XLA phenotype indicates a critical role for Btk in the regulation of B-cell development. However, neither external stimuli leading to Btk activation nor any of its in vivo substrates have thus far been identified, and the mechanism of disease induction remains unexplained. We report here that stimulation of the B-cell antigen receptor (membrane immunoglobulin) on mature B-cells induces tyrosine phosphorylation of Btk in vivo, accompanied by an increase in its kinase activity in vitro. These results place Btk in the B-cell receptor signal transduction pathway, which is known to be essential in driving B-cell differentiation.
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PMID:B-cell antigen receptor stimulation activates the human Bruton's tyrosine kinase, which is deficient in X-linked agammaglobulinemia. 792 28

The genetic defect associated with human X-linked agammaglobulinemia and murine X-linked immunodeficiency was recently shown to result from lack of function of a new cytoplasmic tyrosine kinase, called Bruton's tyrosine kinase (Btk). The phenotypes associated with these immunodeficiencies indicate that Btk plays a critical role in B-lymphocyte development. The distinctive protein structure of Btk and preliminary functional studies suggest that Btk may act in a novel manner in a variety of signaling pathways.
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PMID:Role of Bruton's tyrosine kinase in immunodeficiency. 794 52

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease associated with a block in differentiation from pre-B to B cells. The XLA gene encodes a 659 amino acids cytoplasmic protein tyrosine kinase named btk (Bruton's tyrosine kinase). The few btk gene alterations so far reported in XLA patients are heterogenous and distributed in all domains of the btk protein. They appear to be responsible for a range of B cell immunodeficiency disorders of variable severity. Rare families in which XLA is inherited together with isolated growth hormone deficiency (IGHD) have been reported. Genetic analysis has shown that this disease association maps to the same region of the X chromosome as XLA, but whether the two phenotypes are caused by a common or different developmental or biochemical mechanism is unknown. We have analyzed the btk gene of a patient with XLA and IGHD. RT-PCR analysis of btk transcripts, sequencing data obtained from cDNA and genomic DNA and in vitro splicing assays showed that an intronic point mutation (1882 + 5G-->A) is responsible for skipping of an exon located in the tyrosine kinase domain. This exon-skipping event results in a frameshift leading to a premature stop codon 14 amino acids downstream, and in the loss of the last 61 residues of the carboxy-terminal end of the protein. Although we studied a sporadic case, the results suggest that an alteration of the btk gene might cause this unusual phenotype.
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PMID:An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. 801 27


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