Abstract

X-linked agammaglobulinemia (XLA) is a single gene defect characterized? by profound hypogammaglobulinemia and markedly reduced numbers of B? cells. The abnormal gene product has not yet been identified; however,? studies in the Pi's laboratory have shown that the gene defect is? intrinsic to the B cell lineage and that the gene product is likely to? be expressed throughout B cell differentiation. In the next budget? period the PI plans to identify, isolate and characterize the gene for? XLA. Linkage studies have localized the gene for XLA to a 6-10 mb? segment of the X chromosome. No recombination has been seen with the? probe p2l2 at Xq22, suggesting that the gene defect is likely to be? within 1-2 mb of p2l2.? In the first specific aim, the PI will use pulse field electrophoresis,? yeast artificial chromosomes (YACs), new DNA probes and linkage? analysis to further refine the DNA segment within which the XLA gene? must lie. In preliminary studies, the segment of interest has been? trimmed to 2-3 mb by analysis of recombinant X chromosomes. The? availability of cells and DNA from two unrelated males who are likely? to have deletions of the XLA gene should help further localize the? gene. YACs that encompass the XLA gene locus will be used to generate? new DNA probes.? In the second specific aim, the PI will identify B cell specific? transcripts that are encoded in the XLA gene segment. The methylation? site described above will be characterized in detail. In addition,? phage libraries from overlapping YACs that encompass the XLA gene? segment will be used to screen B cell cDNA libraries.
In specific aim ? three, genomic DNA and/or B cell lineage mRNA from 21 unrelated? patients with XLA will be analyzed with probes that identify XLA gene? candidates. Identification and characterization of the XLA gene will? undoubtedly improve diagnosis and care of affected patients. It should? also increase our understanding of mechanisms involved in normal B cell? differentiation.?

  Funding Agency

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 #
5R37AI025129-21
Application #
7179293
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wedgwood, Josiah F
Project Start
1987-07-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
21
Fiscal Year
2007
Total Cost
$355,568
Indirect Cost

  Institution

Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105

  Publications

Sandlund, J T; Shurtleff, S A; Onciu, M et al. (2013) Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms. Pediatr Blood Cancer 60:E85-7
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
Conley, Mary Ellen (2009) Genetics of hypogammaglobulinemia: what do we really know? Curr Opin Immunol 21:466-71
Conley, Mary Ellen; Dobbs, A Kerry; Farmer, Dana M et al. (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199-227
Winkelstein, Jerry A; Conley, Mary Ellen; James, Cynthia et al. (2008) Adults with X-linked agammaglobulinemia: impact of disease on daily lives, quality of life, educational and socioeconomic status, knowledge of inheritance, and reproductive attitudes. Medicine (Baltimore) 87:253-8
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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