XLA patients with BTK splice-site mutations produce low levels of wild-type BTK transcripts.

X-linked agammaglobulinemia is caused by mutations in the BTK gene, which result in a precursor B-cell differentiation arrest in the bone marrow and the absence of or strongly reduced B lymphocytes in blood. We identified a patient with a mild clinical phenotype, low numbers of B lymphocytes, and a splice-site mutation in the BTK gene. The precursor B-cell compartment in the bone marrow of this patient was almost identical to that in healthy children. Using real-time quantitative polymerase chain reaction, we were able to detect low levels of wild-type BTK transcripts in his granulocytes. Therefore, we speculated that wild-type BTK transcripts might be responsible for a milder clinical and immunological phenotype, as has been shown in several other diseases. Consequently, we quantified the expression of wild-type BTK transcripts in granulocytes of eight additional patients with splice-site mutations and compared their phenotypes with 17 patients with other types of BTK mutations. In these eight patients, the presence of low levels of wild-type BTK transcripts did not show a clear correlation with the percentage, absolute number, or immunophenotype of B lymphocytes nor with age or serum immunoglobulin levels at diagnosis. Nevertheless, we postulate that the presence of wild-type BTK transcripts can be one of the many factors that influence the clinical and immunological phenotype in X-linked agammaglobulinemia.