V(D)J recombination defects in lymphocytes due to RAG mutations: Severe immunodeficiency with a spectrum of clinical presentations

Anna Villa*, Cristina Sobacchi, Luigi D. Notarangelo, Fabio Bozzi, Mario Abinun, Tore G. Abrahamsen, Peter D. Arkwright, Michal Baniyash, Edward G. Brooks, Mary Ellen Conley, Patricia Cortes, Marzia Duse, Anders Fasth, Alexandra M. Filipovich, Anthony J. Infante, Alison Jones, Evelina Mazzolari, Susanna M. Muller, Srdjan Pasic, Gideon RechaviMaria Grazia Sacco, Sandro Santagata, Marlis L. Schroeder, Reinhard Seger, Dario Strina, Alberto Ugazio, Jouni Väliaho, Mauno Vihinen, Larry B. Vogler, Hans Ochs, Paolo Vezzoni, Wilhelm Friedrich, Klaus Schwarz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

297 Scopus citations


Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS: (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.

Original languageAmerican English
Pages (from-to)81-88
Number of pages8
Issue number1
StatePublished - 1 Jan 2001


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