GENETIC ASPECTS OF IMMUNODEFICIENCIES

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DESCRIPTION (Adapted from the Investigator's abstract): The overall goal of this project is to determine the genetic basis of profound defects in B-cell development. The majority of patients with early onset hypoagammaglobulinemia (XLA) who have mutations in the cytoplasmic tyrosine kinase, Btk. There is variability in the severity of the B-cell defect in these patients, even among patients who have null mutations in Btk. This suggests that there are other genetic or environmental factors that influence the severity of disease. The investigator has recently shown that severe defects in B-cell development may also be due to mutations in genes that encode components of the B-cell antigen receptor complex (BRC) or pre-BCR including: mu heavy chains; the surrogate light chain, lambda-5; or the immunoglobulin associated protein, Ig alpha. Several polymorphic variants in these genes have also been identified. The specific aims for the next project period are: 1. Continue to identify and characterize mutations in Btk. The possibility that polymorphic variants of components of the pre-BCR and BCR affect the severity of the B-cell defect in patients with XLA will be examined. 2. Evaluate the functional consequences of mutations identified in the components of the B-cells and the pre-B-cell antigen receptor complex. Using expression vectors in COS cells, the investigator will determine whether the recently identified mutations in lambda-5, Ig alpha or mu heavy chain, result in decreased protein stability, failure to interact with other components of the BCR or if they inhibit signal transduction. 3. Identify and characterize mutations responsible for defects in B-cell development in patients with atypical disease. The identification of the defective genes in patients with immunodeficiency has clinical implications for potential care of affected patients. In addition, the association of immunodeficiency with particular mutations in a well described gene helps elucidate the function of that gene in normal B-cell development.