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A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells


Approximately 90% of patients with isolated agammaglobulinemia 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 agammaglobulinemia 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 heterodimeric 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.

Type Journal
Authors Boisson, B.; Wang, Y. D.; Bosompem, A.; Ma, C. S.; Lim, A.; Kochetkov, T.; Tangye, S. G.; Casanova, J. L.; Conley, M. E.:
Published Date 2013-12-01
Published Volume 123
Published Issue 11
Published Pages 4781-5
Status Published in-print
DOI 10.1172/JCI71927
URL link to publisher's version
OpenAccess link to author's accepted manuscript version