title: Kinase mutant Btk results in atypical X-linked agammaglobulinaemia phenotype.
abstract: 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.
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, University College London, London, UK. h.gaspar@ich.ucl.ac.uk
authors.forename: H B
authors.initials: HB
authors.lastname: Gaspar
authors.forename: M
authors.initials: M
authors.lastname: Ferrando
authors.forename: I
authors.initials: I
authors.lastname: Caragol
authors.forename: M
authors.initials: M
authors.lastname: Hernandez
authors.forename: J M
authors.initials: JM
authors.lastname: Bertran
authors.forename: X
authors.initials: X
authors.lastname: De Gracia
authors.forename: T
authors.initials: T
authors.lastname: Lester
authors.forename: C
authors.initials: C
authors.lastname: Kinnon
authors.forename: E
authors.initials: E
authors.lastname: Ashton
authors.forename: T
authors.initials: T
authors.lastname: Espanol
mesh_terms: D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D004252:DNA Mutational Analysis; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome
chemical_list: D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human