Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan

Abstract

Alterations of the Bruton's tyrosine kinase (Btk) gene are responsible for X-linked agammaglobulinemia (XLA). Although mutations in various regions were reported mainly in the Caucasian population, correlation between the locations of mutation and the clinical phenotypes remains unclear. We report 12 abnormalities of the Btk gene found in 12 unrelated families out of 14 XLA families in Japan and their clinical features. We utilized Southern blotting and single-strand conformation polymorphism (SSCP) analysis. Gene rearrangement in the kinase domain was identified in two patients by Southern blotting. Seven point mutations, two small deletions, and one small insertion were detected by SSCP and sequencing. The SSCP analysis also provided information about the carriers in these families. We found some clinical heterogeneity in the affected family members with the same gene mutation. Moreover, there is considerable inconsistency between the locations of gene aberrations and the immunological phenotypes. Some patients with a nonsense mutation, which may result in the lack of kinase domain, have detectable B cells and immunoglobulins. These identified alterations will provide valuable clues to the Btk protein function and the pathogenesis of XLA.

Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients

“…Moreover, sites R 544 and E589 have been found to be involved in substitutions different from those previously described (Vihinen et al, 1994;Zhu et al,1994;Conley and Rohrer, 1995;Kobayashi et al, 1996). None of those base replacements affect a CpG doublet, that represents a well-known mutation hot spot.…”

Molecular analysis of Bruton’s tyrosine kinase gene in Spain

“…13 out of the 21 mutations (61.9%) are novel (families Nº 1,5,6,7,9,10,11,12,14,17,18,19 and 21) while 8/21 (38 %), have been previously described (Vetrie et al, 1993;Gaspar et al, 1995;Vorechovsky et al, 1995;Kobayashi et al, 1996;Hashimoto S et al, 1996;Vorechovsky et al, 1997;Orlandi et al, 2000). One of the 13 novel mutations found in this study is de novo, because the mother was not a carrier in peripheral blood mononucleated cells.…”

A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation

“…29 The primers used for sequencing were the same as those used for PCR-SSCP. To rule out the possibility of errors caused by Taq DNA polymerase, all mutations were confirmed twice.…”