CHARACTERIZATION OF GERMLINE MUTATIONS OF THE GENE ENCODING BRUTONS TYROSINE KINASE IN FAMILIES WITH X-LINKED AGAMMAGLOBULINEMIA

Bruton's tyrosine kinase (Btk) has been identified as the protein resp onsible for the primary immunodeficiency X-Iinked agammaglobulinemia ( XLA) and has been described as a new member of Src-related cytoplasmic protein tyrosine kinases. We have recently characterized the structur e of the entire gene encoding Btk and developed a polymerase chain rea ction (PCR) based assay to detect germline mutations within it. In thi s report we describe six mutations, five of which are novel, of the Bt k gene in patients with XLA and demonstrate the inheritance pattern of the defect within the families of the affected individuals. The mutat ions found include two nonsense and two missense mutations, a single b ase deletion at an intron acceptor splice site, and a 16-bp insertion. A single strand conformation polymorphism was also found in the 5' en d of intron 8 with the same assay. This technique has provided a power ful tool for direct analysis of the Btk gene for the diagnosis of XLA and carrier detection. The identification of new mutations may eventua lly reveal the role of Btk in the signaling pathways involved in B-cel l development. (C) 1995 Wiley-Liss, Inc.