A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€' B cells
| Autor: | Mary Ellen Conley, Tatiana Kochetkov, Stuart G. Tangye, Bertrand Boisson, Yong-Dong Wang, Cindy S. Ma, Annick Lim, Amma Bosompem, Jean-Laurent Casanova |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Molecular Sequence Data Cell Mutant B-cell receptor Mutation Missense Receptors Antigen B-Cell Biology medicine.disease_cause CD19 Agammaglobulinemia Mutant protein Basic Helix-Loop-Helix Transcription Factors medicine Humans Amino Acid Sequence Receptor B cell Cell Line Transformed Genes Dominant B-Lymphocytes Mutation Base Sequence Sequence Homology Amino Acid Protein Stability Brief Report DNA General Medicine Molecular biology Pedigree medicine.anatomical_structure Amino Acid Substitution biology.protein Female |
| Zdroj: | Journal of Clinical Investigation. 123:4781-4785 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci71927 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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