Patients with genetic defects in B-cell development provide an unusual opportunity to dissect the requirements for normal B-cell maturation. It is striking that all of the known genetic defects that result in a failure of B-cell development involve signaling through the pre-B-cell receptor (pre-BCR). Approximately 85% of affected patients are males with mutations in the X chromosome-encoded cytoplasmic tyrosine kinase Btk. Preliminary experiments using stem cell transplants and retroviral-mediated gene therapy in Btk-deficient mice suggest that it may be relatively easy to correct serum immunoglobulins but harder to correct antibody production to T-cell-independent antigens in this disorder. About 3-6% of patients with defects in B-cell development have deletions or critical base pair substitutions in the mu constant region gene. Patients with defects in Igalpha, lambda5 and B-cell linker protein (BLNK) have also been described. All of these patients have a block at the pro-B to pre-B-cell transition. Defects in Btk, lambda5 and BLNK result in a more severe phenotype in the human compared to the mouse. These findings suggest that requirements for signaling through the pre-BCR are more stringent in the human compared to the mouse. Possible explanations for this observation are discussed.

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.

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