title: Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan.
abstract: Deficiencies of Bruton's tyrosine kinase (Btk) have been implicated in the pathogenesis of human X-linked agammaglobulinemia (XLA). The distinctive phenotype observed in B-cell deficiency indicates the crucial role of Btk in B-cell development. This report describes a nationwide study of Btk deficiency in Japan, covering 51 XLA patients (35 independent families). Along with the identification of mutations, the resulting protein products were characterized by an in vitro kinase assay and a Western blot analysis. Thirty-one of the families were found to have mutations in the coding region of Btk. Although mutations were not found in the cDNA of 4 families, the Btk transcripts of these patients were greatly reduced. The identification of several novel missense mutations, in combination with the result of other studies, clarified the presence of two (missense) mutation hot spots, one in the SH1 and the other in the PH domain. The absence of kinase activity seen in 32 of the families underscored the importance of Btk protein analysis as a diagnostic indicator of XLA. The protein analysis also clarified the different effects of missense mutations on kinase activity and protein stability.
authors.affiliation: Department of Medicine III, Osaka University Medical School, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.forename: S
authors.initials: S
authors.lastname: Tsukada
authors.forename: M
authors.initials: M
authors.lastname: Matsushita
authors.forename: T
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Y
authors.initials: Y
authors.lastname: Niida
authors.forename: A
authors.initials: A
authors.lastname: Yachie
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Iwata
authors.forename: H
authors.initials: H
authors.lastname: Hayakawa
authors.forename: H
authors.initials: H
authors.lastname: Matsuoka
authors.forename: I
authors.initials: I
authors.lastname: Tsuge
authors.forename: T
authors.initials: T
authors.lastname: Yamadori
authors.forename: T
authors.initials: T
authors.lastname: Kunikata
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.forename: K
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D001402:B-Lymphocytes / Q000201:enzymology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion; D014960:X Chromosome / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human