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Transcriptional Regulatory Elements Within the First Intron of
Bruton's Tyrosine Kinase
Jurg Rohrer and
Mary Ellen Conley
From the Department of Immunology, St Jude Children's Research
Hospital; and the Department of Pediatrics, University of Tennessee
College of Medicine, Memphis.
Defects in the gene for Bruton's tyrosine kinase (Btk) result in
the disorder X-linked agammaglobulinemia (XLA). Whereas XLA is
characterized by a profound defect in B-cell development, Btk is
expressed in both the B lymphocyte and myeloid cell lineages. We
evaluated a patient with XLA who had reduced amounts of Btk transcript
but no abnormalities in his coding sequence. A single base-pair
substitution in the first intron of Btk was identified in this patient,
suggesting that this region may contain regulatory elements. Using
reporter constructs we identified two transcriptional control elements
in the first 500 bp of intron 1. A strong positive regulator, active in
both pre-B cells and B cells, was identified within the first 43 bp of
the intron. Gel-shift assays identified two Sp1 binding sites within
this element. The patient's mutation results in an altered binding
specificity of the proximal Sp1 binding site. A negative regulator,
active in pre-B cells only, was located between base pairs 281 and 491 of the intron. These findings indicate that regulation of Btk
transcription is complex and may involve several transcriptional
regulatory factors at the different stages of B-cell differentiation.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 214-221
© 1998 by The American Society of Hematology.
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