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.
Bertrand
B
Boisson
Yong-Dong
YD
Wang
Amma
A
Bosompem
Cindy S
CS
Ma
Annick
A
Lim
Tatiana
T
Kochetkov
Stuart G
SG
Tangye
Jean-Laurent
JL
Casanova
Mary Ellen
ME
Conley
D000361:Agammaglobulinemia / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D055550:Protein Stability; D011947:Receptors, Antigen, B-Cell / Q000172:deficiency*; D017386:Sequence Homology, Amino Acid
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D011947:Receptors, Antigen, B-Cell; C407909:TCF3 protein, human