Background: X-linked agammaglobulinemia (XLA), characterized by the early onset of recurrent bacterial infections, profound hypogammaglobulinemia, and a markedly diminished number of peripheral B lymphocytes, is caused by mutations in the Bruton's tyrosine kinase (BTK) gene. The >600 unique mutations identified to date include single base pair substitutions, small insertions or deletions, and gross deletions. A few cases, however, have been found to have no mutations in the coding region even with reduced BTK mRNA or protein expression. Mutations in intron 1 positions +5 (G-->A) and +6 (T-->G) of the BTK gene have been identified, and these changes were associated with reduced transcriptional activity.
Methods: In the present study a novel mutation in intron 1 position +5 (G-->T) was identified in a Japanese patient with XLA. The reporter constructs containing these mutations were made, and the reporter activities were measured using a luciferase assay.
Results: All the mutant constructs were demonstrated to have reduced transcriptional activity.
Conclusions: Positions +5 and +6 in intron 1 of the BTK gene are critical for transcriptional activity, and defects in these regions cause XLA.