title: Partial V(D)J recombination activity leads to Omenn syndrome.
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.
authors.affiliation: Department of Human Genome and Multifactorial Disease, Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Segrate (Milano) Italy.
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: S
authors.initials: S
authors.lastname: Santagata
authors.forename: F
authors.initials: F
authors.lastname: Bozzi
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: A
authors.initials: A
authors.lastname: Frattini
authors.forename: L
authors.initials: L
authors.lastname: Imberti
authors.forename: L B
authors.initials: LB
authors.lastname: Gatta
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
authors.forename: K
authors.initials: K
authors.lastname: Schwarz
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: E
authors.initials: E
authors.lastname: Spanopoulou
mesh_terms: D000595:Amino Acid Sequence; D017635:Clonal Anergy; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004802:Eosinophilia; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics*; D016654:Genes, RAG-1; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D011995:Recombination, Genetic; D016511:Severe Combined Immunodeficiency / Q000209:etiology* / Q000235:genetics; D013577:Syndrome
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein