Partial V(D)J recombination activity leads to Omenn syndrome.
Genomic rearrangement of the antigen receptor loci is initiated by the two lymphoid-specific proteins Rag-1 and Rag-2. Null mutations in either of the two proteins abrogate initiation of V(D)J recombination and cause severe combined immunodeficiency with complete absence of mature B and T lymphocytes. We report here that patients with ... Omenn syndrome, a severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels, bear missense mutations in either the Rag-1 or Rag-2 genes that result in partial activity of the two proteins. Two of the amino acid substitutions map within the Rag-1 homeodomain and decrease DNA binding activity, while three others lower the efficiency of Rag-1/Rag-2 interaction. These findings provide evidence to indicate that the immunodeficiency manifested in patients with Omenn syndrome arises from mutations that decrease the efficiency of V(D)J recombination.
Mesh Terms:
Amino Acid Sequence, Clonal Anergy, DNA-Binding Proteins, Eosinophilia, Female, Gene Rearrangement, T-Lymphocyte, Genes, RAG-1, Genotype, Homeodomain Proteins, Humans, Lymphocyte Activation, Molecular Sequence Data, Mutation, Nuclear Proteins, Protein Binding, Receptors, Antigen, T-Cell, Recombination, Genetic, Severe Combined Immunodeficiency, Syndrome
Amino Acid Sequence, Clonal Anergy, DNA-Binding Proteins, Eosinophilia, Female, Gene Rearrangement, T-Lymphocyte, Genes, RAG-1, Genotype, Homeodomain Proteins, Humans, Lymphocyte Activation, Molecular Sequence Data, Mutation, Nuclear Proteins, Protein Binding, Receptors, Antigen, T-Cell, Recombination, Genetic, Severe Combined Immunodeficiency, Syndrome
Cell
Date: May. 29, 1998
PubMed ID: 9630231
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