Bruton tyrosine kinase gene mutations in Argentina

Abstract

The block in differentiation from pro-B to pre-B cells results in a selective defect in the humoral immune response characteristic of human X-linked agammaglobulinemia (XLA). Mutations of Bruton tyrosine kinase (BTK) gene have been identified as the cause of XLA. Mutation detection is the most reliable method for making a definitive diagnosis, except when clinical and laboratory findings are distinctive and coupled with history of X-linked inheritance. To provide a definitive diagnosis to 40 families incorporated in the Argentinian Primary Immunodeficiencies Registry we analysed the BTK gene by SSCP analysis as screening method for XLA, followed by direct sequencing. The molecular defect was localized in 45 patients from 34 unrelated families. From the 34 independent mutations identified, 16 were previously undescribed, 31 were unique mutations, 22 were exonic single nucleotide changes (16 missense and 6 nonsense) and four intronic mutations. Because five families had clinical, immunological and inheritance data sufficient for a definitive diagnosis, our study allowed 37 patients from 29 families previously categorized probable/ possible XLA, have now definitive diagnosis leading to appropriate genetic counseling.

A novel Bruton’s tyrosine kinase gene (BTK) invariant splice site mutation in a Malaysian family with X-linked agammaglobulinemia

“…Apart from the mutation described here, a base change or deletion of nucleotides 3' downstream of the invariant donor splice site of intron 9, c.839+4A>G or c.839+(4_7) delAGTA, has also been described elsewhere, resulting in either a frameshift mutation (E280fsx 281) or skipping of exon 9. 15,16,17 The mutation c.838delGAGT involving exon 9 and intron 9 has been described and also resulted in either a frameshift mutation (E280fs) 18 or a skipping of exon 9. 19 In other words, invariant splice donor site of intron 9 may be a hotspot for BTK gene mutation.…”

Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

“…Similar with previously reported cohorts (21,44,60), most of the mutations were found in the kinase domain, emphasizing the significant function of the kinase domain in the B cell development. Of the mutations affecting the kinase domain, the residues Arg520 and Arg525 are arginine-coding CpG dinucleotides that were reported as the frequent mutation sites (61)(62)(63)(64). One of our patients carried p.Arg520Leu mutation and two patients carried p.Arg525* mutation.…”

“…Repetitive DNA sequence, for example, a stretch of seven adenosine nucleotide at positions 209-215 of BTK gene, is vulnerable to replication slippage during DNA replication ( 68 ). During the misalignment, either deletion or addition of nucleotide happens ( 35 , 62 , 69 ) resulting in a non-functional protein. This mutation was also found to be de novo in our patient.…”

“…Other than this mutation, two other point mutations (c.1181C>A and c.1559G>T) were also found to be de novo . Therefore, it is noteworthy to mention that the BTK mutation could occur sporadically ( 3 , 21 , 62 , 63 , 70 , 71 ), although most of the patients inherited the mutation from their mothers.…”

Clinical, immunological and genetic characterization of patients with X‐linked agammaglobulinemia in Costa Rica

“…They were sampled for automated DNA extraction using platform MagNA Pure 2.0 (Roche Diagnostics). Standard PCR protocols, Sanger sequencing 10 and methods established by Danielian et al 13 were used to carry out BTK gene mutational analysis. PCR products were evaluated with a QIAxell system (Qiagen Company) and the mutations were evaluated by Sanger sequencing on an ABI 3130 Genetic Analyser at the University of Costa Rica and ABI 3500 at the National Children´s Hospital and Life Technologies, California, United States by using BigDye 3.1 chemistry.…”