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DELETION WITHIN THE SRC HOMOLOGY DOMAIN-3 OF BRUTON TYROSINE KINASE RESULTING IN X-LINKED AGAMMAGLOBULINEMIA (XLA)

ZHU, QL; ZHANG, M; RAWLINGS, DJ; Vihinen, Mauno LU ; HAGEMANN, T; SAFFRAN, DC; KWAN, SP; NILSSON, L; SMITH, CIE and WITTE, ON, et al. (1994) In Journal of Experimental Medicine 180(2). p.461-470
Abstract
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Journal of Experimental Medicine
volume
180
issue
2
pages
461 - 470
publisher
Rockefeller University Press
external identifiers
  • wos:A1994NZ38500005
  • scopus:0028261105
ISSN
1540-9538
DOI
10.1084/jem.180.2.461
language
English
LU publication?
no
id
baa34c45-97bb-4bef-97ab-48256142ea81 (old id 3853380)
date added to LUP
2013-06-28 14:49:37
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2017-10-15 04:08:55
@article{baa34c45-97bb-4bef-97ab-48256142ea81,
  abstract     = {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.},
  author       = {ZHU, QL and ZHANG, M and RAWLINGS, DJ and Vihinen, Mauno and HAGEMANN, T and SAFFRAN, DC and KWAN, SP and NILSSON, L and SMITH, CIE and WITTE, ON and CHEN, SH and OCHS, HD},
  issn         = {1540-9538},
  language     = {eng},
  number       = {2},
  pages        = {461--470},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {DELETION WITHIN THE SRC HOMOLOGY DOMAIN-3 OF BRUTON TYROSINE KINASE RESULTING IN X-LINKED AGAMMAGLOBULINEMIA (XLA)},
  url          = {http://dx.doi.org/10.1084/jem.180.2.461},
  volume       = {180},
  year         = {1994},
}