The gene responsible for X-linked agammaglobulinemia (XLA) has been recently identified to code for a cytoplasmic tyrosine kinase (Bruton's agammaglobulinemia tyrosine kinase, BTK), required for normal B cell development. BTK, like many other cytoplasmic tyrosine kinases, contains Src homology domains (SH2 and SH3), and catalytic kinase domain. SH3 domains are important for the targeting of signaling molecules to specific subcellular locations. We have identified a family with XLA whose affected members have a point mutation (g-->a) at the 5' splice site of intron 8, resulting in the skipping of coding exon 8 and loss of 21 amino acids forming the COOH-terminal portion of the BTK SH3 domain. The study of three generations within this kinship, using restriction fragment length polymorphism and DNA analysis, allowed identification of the mutant X chromosome responsible for XLA and the carrier status in this family. BTK mRNA was present in normal amounts in Epstein-Barr virus-induced B lymphoblastoid cell lines established from affected family members. Although the SH3 deletion did not alter BTK protein stability and kinase activity of the truncated BTK protein was normal, the affected patients nevertheless have a severe B cell defect characteristic for XLA. The mutant protein was modeled using the normal BTK SH3 domain. The deletion results in loss of two COOH-terminal beta strands containing several residues critical for the formation of the putative SH3 ligand-binding pocket. We predict that, as a result, one or more crucial SH3 binding proteins fail to interact with BTK, interrupting the cytoplasmic signal transduction process required for B cell differentiation.
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1 August 1994
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August 01 1994
Deletion within the Src homology domain 3 of Bruton's tyrosine kinase resulting in X-linked agammaglobulinemia (XLA).
Q Zhu,
Q Zhu
Department of Pediatrics, University of Washington, Seattle 98195.
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M Zhang,
M Zhang
Department of Pediatrics, University of Washington, Seattle 98195.
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D J Rawlings,
D J Rawlings
Department of Pediatrics, University of Washington, Seattle 98195.
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M Vihinen,
M Vihinen
Department of Pediatrics, University of Washington, Seattle 98195.
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T Hagemann,
T Hagemann
Department of Pediatrics, University of Washington, Seattle 98195.
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D C Saffran,
D C Saffran
Department of Pediatrics, University of Washington, Seattle 98195.
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S P Kwan,
S P Kwan
Department of Pediatrics, University of Washington, Seattle 98195.
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L Nilsson,
L Nilsson
Department of Pediatrics, University of Washington, Seattle 98195.
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C I Smith,
C I Smith
Department of Pediatrics, University of Washington, Seattle 98195.
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O N Witte,
O N Witte
Department of Pediatrics, University of Washington, Seattle 98195.
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S H Chen,
S H Chen
Department of Pediatrics, University of Washington, Seattle 98195.
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H D Ochs
H D Ochs
Department of Pediatrics, University of Washington, Seattle 98195.
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Q Zhu
Department of Pediatrics, University of Washington, Seattle 98195.
M Zhang
Department of Pediatrics, University of Washington, Seattle 98195.
D J Rawlings
Department of Pediatrics, University of Washington, Seattle 98195.
M Vihinen
Department of Pediatrics, University of Washington, Seattle 98195.
T Hagemann
Department of Pediatrics, University of Washington, Seattle 98195.
D C Saffran
Department of Pediatrics, University of Washington, Seattle 98195.
S P Kwan
Department of Pediatrics, University of Washington, Seattle 98195.
L Nilsson
Department of Pediatrics, University of Washington, Seattle 98195.
C I Smith
Department of Pediatrics, University of Washington, Seattle 98195.
O N Witte
Department of Pediatrics, University of Washington, Seattle 98195.
S H Chen
Department of Pediatrics, University of Washington, Seattle 98195.
H D Ochs
Department of Pediatrics, University of Washington, Seattle 98195.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1994) 180 (2): 461–470.
Citation
Q Zhu, M Zhang, D J Rawlings, M Vihinen, T Hagemann, D C Saffran, S P Kwan, L Nilsson, C I Smith, O N Witte, S H Chen, H D Ochs; Deletion within the Src homology domain 3 of Bruton's tyrosine kinase resulting in X-linked agammaglobulinemia (XLA).. J Exp Med 1 August 1994; 180 (2): 461–470. doi: https://doi.org/10.1084/jem.180.2.461
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