Mutations of the humanBTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia

Vihinen, Mauno; Kwan, SP; Lester, Tracy; Hd, Ochs; Resnick, Igor B.; Väliaho, Jouni; Conley, ME; Smith, C. I. Edvard

doi:10.1002/(sici)1098-1004(1999)13:4<280::aid-humu3>3.0.co;2-l

Cited by 105 publications

(68 citation statements)

References 33 publications

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“…[Vihinen et al, 1994a[Vihinen et al, ,b, 1995[Vihinen et al, , 1997[Vihinen et al, , 1999), SH2 domain protein 1A (SH2D1A) mutations in X-linked lymphoproliferative disease [Lappalainen et al, 2000], Bloom syndrome protein (BLM) mutations in Bloom syndrome , mutations in the Wiscott-Aldrich syndrome protein (WAS) protein in Wiskott-Aldrich syndrome , mutations in the methyltransferase (DNMT3B) in immunodeficiency, centromeric instability, and facial abnormalities (ICF) syndrome [Lappalainen and Vihinen, 2002], and CD40L mutations in X-linked hyperimmunoglobulin M (hyper-IgM) syndrome (Thusberg, J., and Vihinen, M., unpublished results). We utilize experience gained in all these studies to discuss the effects of mutations and also the use and applicability of different methods.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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“…Btk is the only member of the Tec family kinases in which mutations have been found to be associated with a disease (7,47,48). Intriguingly, point mutations of the highly conserved aromatic residues in the caveolin-binding motif within the catalytic domain of Btk have been detected in patients with classical XLA (Table I) (7).…”

Section: Discussionmentioning

confidence: 99%

Functional Interaction of Caveolin-1 with Bruton's Tyrosine Kinase and Bmx

Vargas¹,

Nore²,

Berglöf³

et al. 2002

Journal of Biological Chemistry

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Bruton's tyrosine kinase (Btk), a member of the Tec family of protein-tyrosine kinases, has been shown to be crucial for B cell development, differentiation, and signaling. Mutations in the Btk gene lead to X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice. Using a co-transfection approach, we present evidence here that Btk interacts physically with caveolin-1, a 22-kDa integral membrane protein, which is the principal structural and regulatory component of caveolae membranes. In addition, we found that native Bmx, another member of the Tec family kinases, is associated with endogenous caveolin-1 in primary human umbilical vein endothelial cells. Second, in transient transfection assays, expression of caveolin-1 leads to a substantial reduction in the in vivo tyrosine phosphorylation of both Btk and its constitutively active form, E41K. Furthermore, a caveolin-1 scaffolding peptide (amino acids 82-101) functionally suppressed the autokinase activity of purified recombinant Btk protein. Third, we demonstrate that mouse splenic B-lymphocytes express substantial amounts of caveolin-1. Interestingly, caveolin-1 was found to be constitutively phosphorylated on tyrosine 14 in these cells. The expression of caveolin-1 in B-lymphocytes and its interaction with Btk may have implications not only for B cell activation and signaling, but also for antigen presentation.

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“…Mutations in the SH2 domain of Btk are associated with impaired B cell function and may cause the XLA immunode®ciency in humans, possibly due to disruption of phosphotyrosine binding sites (Vihinen et al, 1999). Several proteins have been shown to interact with the SH2 domains of Btk kinases and to modulate their functions.…”

Section: Sh2 Domainmentioning

confidence: 99%

Signaling network of the Btk family kinases

Qiu¹,

2000

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The Btk family kinases represent new members of nonreceptor tyrosine kinases, which include Btk/Atk, Itk/ Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Srcfamily kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCg and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, di erentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunode®ciency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the di erent modules of the kinases and the diverse signaling pathways in which they are involved. Oncogene (2000) 19, 5651 ± 5661.

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Mutations of the humanBTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia

Cited by 105 publications

References 33 publications

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Functional Interaction of Caveolin-1 with Bruton's Tyrosine Kinase and Bmx

Signaling network of the Btk family kinases

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