Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 11, Pages 4781-4785Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI71927
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Funding
- Le Bonheur Research Funds
- Federal Express Chair of Excellence
- National Cancer Institute [P30 CA21765]
- American Lebanese Syrian Associated Charities
- National Health and Medical Research Council of Australia
- St. Giles Foundation
- National Center for Research Resources
- National Center for Advancing Sciences (NCATS) [8UL1TR000043]
- Rockefeller University
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Approximately 90% of patients with isolated agammaglob ulinemia and failure of B cell development have mutations in genes required for signaling through the pre-B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agatnmaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heteroclimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.
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