BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients
نویسندگان
چکیده
Mutations in the Bruton agammaglobulinemia tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). Unfolded or misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER), known as unfolded protein response (UPR). The aim was to clarify the involvement of UPR in XLA pathophysiology. By reverse transcription-quantitative PCR, we evaluated the expression of BTK and 12 UPR-related genes in eight patients. Moreover, we assessed the BTK protein expression and pattern in the patients' monocytes by flow cytometry and fluorescence immunocytochemistry. We found a reduced BTK expression in patients with stop codon mutations (P < 0.02). However, missense mutations did not affect BTK expression. Flow cytometry showed a reduction of BTK in patients which was corroborated by an absent or nonfunctional protein synthesis revealed by immunocytochemistry. In contrast with the other UPR-related genes, X-box binding protein 1 (XBP1) was markedly upregulated in the patients (P < 0.01), suggesting Toll-like receptor (TLR) activation since BTK directly interacts with TLRs as a negative regulator and XBP1 can be activated in direct response to TLR ligation. Different BTK mutations can be identified by the BTK expression. Inasmuch as UPR-related genes were downregulated or unaltered in patients, we speculate the involvement of the TLRs-XBP1 axis in the XLA pathophysiology. Such data could be the basis for further studies of this novel pathomechanism concerning XLA.
منابع مشابه
Deficient Expression of Bruton's Tyrosine Kinase in Monocytes from X-Linked Agammaglobulinemia as Evaluated by a Flow Cytometric Analysis and its Clinical Application to Carrier Detection
Background: The B-cell defect in X-linked agammaglobulinemia (XLA) is caused by mutations in the gene for Bruton's tyrosine kinase (BTK). BTK mutations result in deficient expression of BTK protein in peripheral blood monocytes. Methods: Using the anti-BTK monoclonal antibody (48-2H), a flow cytometric analysis of intra cytoplasmic BTK protein expression in monocytes was performed to identify I...
متن کاملرابطهی عدم بیان پروتئین تیروزینکیناز بروتون و بروز جهش در نواحی غیرکدکنندهی ژن, در بیماران آگاماگلوبولینمی وابسته به جنس
Correlation of Null Btk Expression and Gene Noncoding Mutations in XLA Patients Nasseri S1, Sorouri R2, Pourpak Z3, Rezaei N4, Moin M5, Parvaneh N6, Aghamohammadi A7 1 Dept of Molecular Biology, Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran 2 Baqiyatallah University of Medical Sciences, Tehran, Iran and, Zanjan University of Medical Scien...
متن کاملDeficient expression of Bruton's tyrosine kinase in monocytes from X-linked agammaglobulinemia as evaluated by a flow cytometric analysis and its clinical application to carrier detection.
The B-cell defect in X-linked agammaglobulinemia (XLA) is caused by mutations in the gene for Bruton's tyrosine kinase (BTK). Using the anti-BTK monoclonal antibody (48-2H), a flow cytometric analysis of intracytoplasmic BTK protein expressed in monocytes was successfully performed. To examine the possible identification of XLA patients and female carriers by this assay, we studied 41 unrelated...
متن کاملSplice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.
X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Bot...
متن کاملSplice-Correction Strategies for Treatment of X-Linked Agammaglobulinemia
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). Deficiency of BTK leads to a developmental block in B cell differentiation; hence, the patients essentially lack antibody-producing plasma cells and are susceptible to various infections. A substantial portion of the mutations in BTK results in splic...
متن کامل