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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI025129-16
Application #
6497246
Study Section
Immunobiology Study Section (IMB)
Program Officer
Esch, Thomas R
Project Start
1987-07-01
Project End
2003-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
16
Fiscal Year
2002
Total Cost
$288,337
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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Conley, Mary Ellen; Dobbs, A Kerry; Quintana, Anita M et al. (2012) Agammaglobulinemia and absent B lineage cells in a patient lacking the p85? subunit of PI3K. J Exp Med 209:463-70
Dobbs, A Kerry; Bosompem, Amma; Coustan-Smith, Elaine et al. (2011) Agammaglobulinemia associated with BCRýýý B cells and enhanced expression of CD19. Blood 118:1828-37
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Conley, M E; Farmer, D M; Dobbs, A K et al. (2008) A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol 152:39-44
Dobbs, A Kerry; Yang, Tianyu; Farmer, Dana et al. (2007) Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J Immunol 179:2055-9
Dobbs, A K; Yang, T; Farmer, D M et al. (2007) A possible bichromatid mutation in a male gamete giving rise to a female mosaic for two different mutations in the X-linked gene WAS. Clin Genet 71:171-6
Howard, Vanessa; Greene, Jeffrey M; Pahwa, Savita et al. (2006) The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol 118:201-8

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