J. Exp. Med., Volume 188, Number 4, August 17, 1998 627-634

A Human Severe Combined Immunodeficiency (SCID) Condition with Increased Sensitivity to Ionizing Radiations and Impaired V(D)J Rearrangements Defines a New DNA Recombination/Repair Deficiency

By Nathalie Nicolas,^* Despina Moshous,^* Marina Cavazzana-Calvo,^* Dora Papadopoulo, Régina de Chasseval,^* Françoise Le Deist,^* Alain Fischer,^* and Jean-Pierre de Villartay^*

From the ^* Institut National de la Santé et de la Recherche Médicale U429, Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, 75015 Paris, France; and  Centre National de la Recherche Scientifique Unité Mixte de Recherche 218 Institut Curie-Section Recherche, 75005 Paris, France

The products of recombination activating gene (RAG)1 and RAG2 initiate the lymphoid-specific phase of the V(D)J recombination by creating a DNA double-strand break (dsb), leaving hairpin-sealed coding ends. The next step uses the general DNA repair machinery of the cells to resolve this dsb. Several genes involved in both V(D)J recombination and DNA repair have been identified through the analysis of in vitro mutants (Chinese hamster ovary cells) and in vivo situations of murine and equine severe combined immunodeficiency (scid). These studies lead to the description of the Ku-DNA-dependent protein kinase complex and the XRCC4 factor. A human SCID condition is characterized by an absence of B and T lymphocytes. One subset of these patients also demonstrates an increased sensitivity to the ionizing radiation of their fibroblasts and bone marrow precursor cells. This phenotype is accompanied by a profound defect in V(D)J recombination with a lack of coding joint formation, whereas signal joints are normal. Functional and genetic analyses distinguish these patients from the other recombination/repair mutants, and thus define a new group of mutants whose affected gene(s) is involved in sensitivity to ionizing radiation and V(D)J recombination.

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