Variations in the human phospholipase C gamma 2 gene in patients with B-cell defects of unknown etiology

Our recent studies using targeted gene disruption have shown that defects in phospholipase C gamma 2 (PLC gamma 2) result in a B-cell abnormality that is very similar to that seen in Btk-deficient mice. Null mutations in eitherPLCG2 orBTK are associated with decreased numbers of mature B cells, failure to make antibodies to some T cell-independent antigens and the absence of CD5 super(+) peritoneal B cells. Mutations inBTK 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 inBTK 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 inPLCG2, 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.