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A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR– B cells
Bertrand Boisson, … , Jean-Laurent Casanova, Mary Ellen Conley
Bertrand Boisson, … , Jean-Laurent Casanova, Mary Ellen Conley
Published October 15, 2013
Citation Information: J Clin Invest. 2013;123(11):4781-4785. https://doi.org/10.1172/JCI71927.
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Brief Report Genetics

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR– B cells

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Abstract

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.

Authors

Bertrand Boisson, Yong-Dong Wang, Amma Bosompem, Cindy S. Ma, Annick Lim, Tatiana Kochetkov, Stuart G. Tangye, Jean-Laurent Casanova, Mary Ellen Conley

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Figure 1

The E555K mutation in E47.

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The E555K mutation in E47.
(A) The pedigrees of the 4 patients are shown...
(A) The pedigrees of the 4 patients are shown. Squares denote males, circles denote females, and black symbols indicate affected patients. (B) Schematic diagrams of the E2A intron/exon structure (top) and the protein structure (bottom) are depicted. The exons and domains specific for E12 and E47 are shown in blue and red, respectively. The functional domains of the proteins, the activation domains 1 and 2 (AD1 and AD2), and the bHLH domain are shaded in gray; exons are numbered. (C) The specific base pair and amino acid alterations seen in the patients are shown. (D) The conservation of the glutamic acid at codon 555 is demonstrated.

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