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Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling.

Lindvall, Jessica M; Blomberg, K Emelie M; Väliaho, Jouni; Vargas, Leonardo; Heinonen, Juhana E; Berglöf, Anna; Mohamed, Abdalla J; Nore, Beston F; Vihinen, Mauno LU and Smith, C I Edvard (2005) In Immunological Reviews 203. p.200-215
Abstract
Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B-lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full-length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only... (More)
Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B-lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full-length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype-phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering-RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA-, Xid-, and Btk-knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid- and Btk-KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C-missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Protein-Tyrosine Kinases: metabolism, Protein-Tyrosine Kinases: genetics, Protein-Tyrosine Kinases: chemistry, Agammaglobulinemia: genetics, Immunologic Deficiency Syndromes: genetics, RNA, Small Interfering: genetics
in
Immunological Reviews
volume
203
pages
200 - 215
publisher
Munksgaard International Publishers
external identifiers
  • PMID:15661031
  • Scopus:19944434293
ISSN
1600-065X
DOI
10.1111/j.0105-2896.2005.00225.x
language
English
LU publication?
no
id
274a2243-74ed-48a8-94e6-ae136f5477aa (old id 3635428)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/15661031?dopt=Abstract
date added to LUP
2013-06-12 16:15:47
date last changed
2016-10-13 04:29:29
@misc{274a2243-74ed-48a8-94e6-ae136f5477aa,
  abstract     = {Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B-lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full-length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P &lt; 0.001). Although genotype-phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering-RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA-, Xid-, and Btk-knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid- and Btk-KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C-missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.},
  author       = {Lindvall, Jessica M and Blomberg, K Emelie M and Väliaho, Jouni and Vargas, Leonardo and Heinonen, Juhana E and Berglöf, Anna and Mohamed, Abdalla J and Nore, Beston F and Vihinen, Mauno and Smith, C I Edvard},
  issn         = {1600-065X},
  keyword      = {Protein-Tyrosine Kinases: metabolism,Protein-Tyrosine Kinases: genetics,Protein-Tyrosine Kinases: chemistry,Agammaglobulinemia: genetics,Immunologic Deficiency Syndromes: genetics,RNA,Small Interfering: genetics},
  language     = {eng},
  pages        = {200--215},
  publisher    = {ARRAY(0xa101e98)},
  series       = {Immunological Reviews},
  title        = {Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling.},
  url          = {http://dx.doi.org/10.1111/j.0105-2896.2005.00225.x},
  volume       = {203},
  year         = {2005},
}