MUTATION PATTERN IN BRUTON TYROSINE KINASE GENE IN 26 UNRELATED PATIENTS WITH X-LINKED AGAMMAGLOBULINEMIA

Mutation pattern was characterized in the Bruton's tyrosine kinase gen e (BTK) in 26 patients with X-linked agammaglobulinemia, the first des cribed immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations w ere found to result in premature termination of the translation produc t. Mutations were detected in most BTK exons with a predominance of fr ameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of th e enzyme, Nonsense and frameshift mutations were associated with dimin ished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitut ion (R28H) was found in the pleckstrin homology do-main's residue, whi ch is mutated in mice bearing the X-linked immunodeficiency phenotype; another substitution (R307G) was identified in the src homology domai n 2, All remaining amino acid substitutions were found in the catalyti c domain of Btk. (C) 1997 Wiley-Liss, Inc.