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 eit her of the two proteins abrogate initiation of V(D)J recombination and cause severe combined immunodeficiency with complete absence of matur e B and T rymphocytes. We report here that patients with Omenn syndrom e, a severe immunodeficiency characterized by the presence of activate d, anergic, oligoclonal T cells, hypereosinophilia, and high IgE level s, bear missense mutations in either the Rag-1 or Rag-2 genes that res ult in partial activity of the two proteins. Two of the amino acid sub stitutions map within the Rag-1 homeodomain and decrease DNA binding a ctivity, while three others lower the efficiency of Rag-1/Rag-2 intera ction. These findings provide evidence to indicate that the immunodefi ciency manifested in patients with Omenn syndrome arises from mutation s that decrease the efficiency of V(D)J recombination.