A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection

J Clin Invest. 2005 Nov;115(11):3291-9. doi: 10.1172/JCI25178.


Amorphic mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause T- B- SCID, whereas hypomorphic mutations led to the expansion of a few autoimmune T cell clones responsible for the Omenn syndrome phenotype. We report here a novel clinical and immunological phenotype associated with recessive RAG1 hypomorphic mutations in 4 patients from 4 different families. The immunological phenotype consists of the oligoclonal expansion of TCR gammadelta T cells combined with TCR alphabeta T cell lymphopenia. The clinical phenotype consists of severe, disseminated CMV infection and autoimmune blood cell manifestations. Repertoire studies suggest that CMV infection, in the setting of this particular T cell immunodeficiency, may have driven the TCR gammadelta T cell clonal expansion. This observation extends the range of clinical and immunological phenotypes associated with RAG mutations, emphasizing the role of the genetic background and microbial environment in determining disease phenotype.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Consanguinity
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / genetics
  • Cytomegalovirus Infections / immunology*
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
  • Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
  • Homeodomain Proteins / genetics*
  • Homozygote
  • Humans
  • Immunophenotyping
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Severe Combined Immunodeficiency / genetics*


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • V(D)J recombination activating protein 2
  • RAG-1 protein

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