Partial V(D)J Recombination Activity Leads to Omenn Syndrome
1998; Cell Press; Volume: 93; Issue: 5 Linguagem: Inglês
10.1016/s0092-8674(00)81448-8
ISSN1097-4172
AutoresAnna Villa, Sandro Santagata, Fabio Bozzi, Silvia Giliani, Annalisa Frattini, Luisa Imberti, Luisa Benerini Gatta, Hans D. Ochs, Klaus Schwarz, Luigi D. Notarangelo, Paolo Vezzoni, Eugenia Spanopoulou,
Tópico(s)T-cell and B-cell Immunology
ResumoGenomic 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.
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