Variations in the human phospholipase Cγ2 gene in patients with B-cell defects of unknown etiology

Abstract

Our recent studies using targeted gene disruption have shown that defects in phospholipase Cgamma2 (PLCgamma2) result in a B-cell abnormality that is very similar to that seen in Btk-deficient mice. Null mutations in either PLCG2 or BTK are associated with decreased numbers of mature B cells, failure to make antibodies to some T cell-independent antigens and the absence of CD5+ peritoneal B cells. Mutations in BTK in humans cause a more severe defect in B-cell development characterized by almost complete absence of B cells in the peripheral circulation, profound hypogammaglobulinemia and an inability to produce antibodies to any antigens. However, not all patients with severe defects in B-cell development have mutations in BTK or the components of the B-cell signal transduction complex. To explore the possibility that some patients with defects in B-cell development of unknown etiology might have mutations in PLCG2, we determined the genomic structure of this gene and established conditions to analyze the 32 exons of the gene and the flanking sequences by single-strand conformation polymorphism. Although 24 polymorphic variants of this gene were found in 35 patients, we did not identify any alterations that were likely to be the cause of disease.

Association study with Wegener granulomatosis of the human phospholipase Cγ2 gene

“…Exon 12 revealed a low frequent SNP (1122G>A), which represents the first base pair of the exon. In exon 13 two previously identified SNPs (1293T>C and 1296T>C) were detected [18]. Both SNPs showed similar frequencies as reported [18].…”

“…In exon 13 two previously identified SNPs (1293T>C and 1296T>C) were detected [18]. Both SNPs showed similar frequencies as reported [18]. All variations were found not significantly different in WG patients compared to the control group, and they were not associated with amino acid substitutions.…”

“…Our study revealed 4 single base substitutions, 2 of which were reported before [18]. A further silent and low frequent SNP was detected in exon 12 which did not differ significantly between patient and control cohorts after PCR/RFLP analyses.…”

“…The 4.2 kb mRNA consists of 33 Exon coding for a M r 140,000 protein with 1265 amino acids [17]. PLCγ-2 is highly polymorphic [18]. …”

Essential, Nonredundant Role for the Phosphoinositide 3-Kinase p110δ in Signaling by the B-Cell Receptor Complex

“…It might be anticipated that other components, identified through gene disruptions in mice, would contribute to those cases in which an etiology is not known. Recent studies (34), however, failed to identify causative mutations in PLC␥2 in 32 such cases. It should be noted, however, that the deficiency of PLC␥2 in mice affects many receptors of the immunoglobulin superfamily, including the collagen receptor complex on platelets, and therefore a spectrum of phenotypic changes would be expected in individuals with a deficiency in PLC␥2.…”