X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase

Smith, C. I. Edvard; Backesjo, CM; Berglöf, Anna; Branden, Lars; Islam, Tahmina; Mattsson, PT; Mohamed, Abdalla J.; Müller, Susanne; Nore, Beston F.; Vihinen, Mauno

doi:10.1007/bf00792597

Cited by 25 publications

(16 citation statements)

References 107 publications

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“…The structures of the other domains have been modelled [Zhu et al, 1993;Vihinen et al, 1994aVihinen et al, ,b, 1995a]. The consequences of all the mutations have been studied based on structural information [Zhu et al, 1993;Vihinen et al, 1994aVihinen et al, ,b, 1995aVihinen et al, ,b, 1998].…”

Section: The Btk Gene and Its Productmentioning

confidence: 99%

“…X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene coding for Bruton agammaglobulinemia tyrosine kinase (BTK; MIM# 300300) [Vetrie et al, 1993;Tsukada et al, 1993]. XLA is caused by a block in B-cell differentiation resulting in severely decreased numbers of B lymphocytes and by an almost complete lack of plasma cells, as well as by negligible or very low immunoglobulin levels of all isotypes Smith et al, 1998]. The patients have increased susceptibility to mainly bacterial infections because of virtually absent humoral immune responses.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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X‐linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations lists 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms have been found. Mutations in all the five domains of BTK cause the disease, the single most common event being missense mutations. Most mutations lead to truncation of the enzyme. The mutations appear almost uniformly throughout the molecule. About one‐third of point mutations affect CpG sites, which usually code for arginine residues. The putative structural implications of all the missense mutations are provided in the database. BTKbase is available at http://www.uta.fi/imt/bioinfo. Hum Mutat 13:280–285, 1999. © 1999 Wiley‐Liss, Inc.

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Section: The Btk Gene and Its Productmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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“…Bruton's tyrosine kinase (Btk) is a kinase expressed exclusively in B cells and myeloid cells and has a well characterized, vital role in B cells highlighted by the human primary immune deficiency disease, X-linked agammaglobulinemia (XLA), which results from mutation in the Btk gene (Smith et al, 1998). As a result of incomplete B cell differentiation, XLA patients have a near complete absence of mature B cells in the peripheral blood (Campana et al, 1990) and cannot produce immunoglobulins (Conley, 1985;Nonoyama et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans

Evans¹,

Tester²,

Aslanian³

et al. 2013

J Pharmacol Exp Ther

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Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

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“…XLA originates from a block in B-cell differentiation resulting in severely decreased numbers of B lymphocytes and an almost complete lack of plasma cells, as well as negligible, or very low, immunoglobulin levels of all isotypes Smith et al, 1998]. XLA patients have increased susceptibility to mainly bacterial infections due to virtually absent humoral immune responses.…”

Section: Introductionmentioning

confidence: 99%

BTKbase: the mutation database for X-linked agammaglobulinemia

Väliaho¹,

Smith²,

Vihinen³

2006

Hum. Mutat.

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For the Immunogenetics Special IssueX-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). XLA patients have a decreased number of mature B cells and a lack of all immunoglobulin isotypes, resulting in susceptibility to severe bacterial infections. XLA-causing mutations are collected in a mutation database (BTKbase), which is available at http://bioinf.uta.fi/BTKbase. For each patient the following information is given (when available): the identification of the entry, a plain English description of the mutation followed by a reference, formal characterization of the mutation, and the various parameters from the patient. BTKbase is implemented with the MUTbase program suite, which provides an easy, interactive, and quality controlled submission of information to mutation databases.

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X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase

Cited by 25 publications

References 107 publications

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

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

Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans

BTKbase: the mutation database for X-linked agammaglobulinemia

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