Kinase mutant Btk results in atypical X-linked agammaglobulinaemia phenotype

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  • H B Gaspar
    Molecular Immunology Unit, Institute of Child Health, University College London, London, UK
  • M Ferrando
    Immunology and Immunodeficiencies Unit and
  • I Caragol
    Immunology and Immunodeficiencies Unit and
  • M Hernandez
    Immunology and Immunodeficiencies Unit and
  • J M Bertran
    Immunology and Immunodeficiencies Unit and
  • X De gracia
    Pneumonology Service, Hospitals Vall d’Hebron, Barcelona, Spain
  • T Lester
    Clinical Molecular Genetics Laboratory, Great Ormond Street Hospital NHS Trust, London, UK
  • C Kinnon
    Molecular Immunology Unit, Institute of Child Health, University College London, London, UK
  • E Ashton
    Molecular Immunology Unit, Institute of Child Health, University College London, London, UK
  • T Espanol
    Immunology and Immunodeficiencies Unit and

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<jats:title>SUMMARY</jats:title> <jats:p>X-linked agammaglobulinaemia (XLA) is a B cell humoral abnormality arising from mutations in the gene encoding Bruton’s tyrosine kinase (Btk). The phenotype of XLA can be variable, with some individuals having a less severe immunophenotype, although in most cases this cannot be correlated with the Btk mutation or expression of Btk protein. In this study we describe clinical and immunological heterogeneity within the same pedigree. Analysis of the genetic defect identified a missense mutation in the kinase domain of Btk which, unusually, preserved Btk protein expression but at reduced levels, and also considerably diminished autophosphorylation activity. Structural analysis of the effect of this mutation on the kinase domain suggests that this mutation is not an integral part of the ATP or substrate binding domains but may affect the interaction of the kinase domain with its own kinase domain and other substrates. Together, these data may provide an explanation for the variable XLA phenotype.</jats:p>

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