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X-linked agammaglobulinemia (XLA) is an immunodeficiency disorder caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). In this study we investigated 10 male patients with XLA-compatible phenotype (agammaglobulinemia and undetectable B cells in peripheral blood) from 9 unrelated Central European families. We identified seven different mutations, six of which were novel. One previously described point mutation caused a premature stop codon (p.C464X), two point mutations resulted in amino acid exchanges (p.W588R; p.G419E), and two point mutations affected splice sites (c.305-1G>A; c.391+1G>A). We further detected one deletion (c.1921_1927del CGTCCCA) and one large duplication. The duplication resulted from Alu element-induced unequal homologous recombination, which was only detectable by extended analysis of cDNA, while direct sequencing of genomic DNA gave a false negative result. Western blot analysis revealed that the patients with the p.W588R and the p.G419E amino acid substitutions, respectively, produced full length BTK, but in clearly diminished amounts. The patient with the 7bp deletion expressed low amounts of protein which might represent truncated BTK. All other genomic alterations resulted in complete loss of BTK protein. In two patients from unrelated families BTK protein expression was normal and no Btk gene mutation was detected. The results of this study further substantiate the importance of using elaborate molecular analysis with different detection techniques to obtain an explicit molecular diagnosis in patients with suspected XLA.
Pubmed ID: 17045652
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A mutation registry for X-linked agammaglobulinemia (XLA). BTKbase lists mutation entries of 1,111 patients from 973 unrelated families showing 602 unique molecular events. Agammaglobulinemia is characterized by failure to produce mature B lymphocyte cells and is associated with a failure of Ig heavy chain rearrangement. Two thirds of cases are familial, and one third of cases are believed to arise from new mutations. Mutations of the BTK gene are found in approximately 80% of patients with agammaglobulinemia. The localization of the mutations on the gene and protein for BTK can be analyzed by clicking sequences on the web pages. It includes a mutation browser, which gives users access to mutations in Bruton tyrosine kinase (BTK) protein sequences, and XLA fact file, and forms for users to submit mutation to the dataset.
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