Bruton's tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA.

Mutations in the Bruton's tyrosine kinase (BTK) gene result in XLA. Despite the large numbers of BTK mutations reported, no correlation can be made between the clinical phenotype and the gene defects. Analysis of Btk protein expression and activity in individuals with XLA was performed to characterize the relationship between a particular mutation, the resultant Btk protein and the clinical phenotype. In most patients studied, including those with atypical phenotypes, there was complete absence of protein expression and activity. Furthermore, in two undiagnosed individuals with a clinical phenotype suggestive of XLA, lack of protein expression was used to confirm an abnormality in Btk. These results underline the importance of protein analysis prior to speculating on protein structure and function based on the gene mutation. Lack of Btk expression in atypical phenotypes suggests that there is redundancy in B lymphocyte signalling such that alternative signalling molecules, or mechanisms, can compensate for the lack of Btk. We also suggest that analysis of Btk expression can be used as an indicator of XLA. These rapid assays may be used to screen a wider spectrum of individuals with humoral immunodeficiency in order to characterize fully the extent of Btk deficiency.