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Our results demonstrate a predominantly inflammatory response in XLA patients after LPS stimulation and suggest a deregulation of TLR signaling in the absence of Btk. This response may be influenced by environmental factors.

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These results suggest that in some patients, the combined defects in both T and B-cells may account for CVID. Additionally, patients in group I exhibited an increased frequency of pneumonia and chronic diarrhoea.

SummaryBruton agammaglobulinemia tyrosine kinase (BTK) is a key protein in the B-cell receptor (BCR) signaling pathway and plays an essential role in the differentiation of B lymphocytes. X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency caused by mutations in the gene encoding BTK. Previously, we identified two novel variations, L111P and E605G, in BTK; these are localized within the pleckstrin homology and Src homology 1 domains, respectively. In the present study, we evaluated the potential effects of these variations on the structural conformation and the function of BTK. Using in silico methods, we found that the L111P and E650G variations are not located directly in protein-protein interfaces but close to them. They distorted the native structural conformation of the BTK protein, affecting not only its geometry and stability but also its ability for protein recognition and in consequence its functionality. To confirm the results of the in silico assays, WT BTK, L111P, and E650G variants were expressed in the BTK-deficient DT40 cell line. The mutant proteins exhibited an absence of catalytic activity, aberrant redistribution after BCR-crosslinking, and deficient intracellular calcium mobilization. This work demonstrates that L111 and E605 residues are fundamental for the activation and function of BTK.2012 IUBMB IUBMB Life, 64(4): [346][347][348][349][350][351][352][353] 2012

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency originated from mutations in the gene encoding Bruton's tyrosine Kinase (Btk). Btk is a vital protein in the B cell signaling machinery. L111P and E605G are two recently characterized mutations in Mexican patients suffering XLA; they gave us the basis for a more detailed study of the effects of these mutations in the conformation and functionality of Btk. In silico assays showed that L111 and E605 residues are fundamental for the activations and functionality of the Btk. Btk from the two patients and a healthy control were expressed in the Btk-deficient DT40 cell line, in order to confirm the predictions obtained in silico. The absence of the Btk catalytic activity of the patients was reflected in the lack of the Y551 phosphorylation. This may resulted in a reduced activation of PLC-ã2 that was reflected by reduction of intracellular calcium flux. This work show that L111 and E605 residues are fundamental in the structural conformation of the Btk and that in silico analysis can be a useful tool for the analysis of Btk mutations found in primary immunodeficiency patients. Supported by CONACyT, project No. 70062