Partial V(D)J recombination activity leads to omenn syndrome

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Abstract

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.

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Villa, A., Santagata, S., Bozzi, F., Giliani, S., Frattini, A., Imberti, L., … Spanopoulou, E. (1998). Partial V(D)J recombination activity leads to omenn syndrome. Cell, 93(5), 885–896. https://doi.org/10.1016/S0092-8674(00)81448-8

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