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J Biol Chem, Vol. 275, Issue 17, 12672-12675, April 28, 2000

Three-dimensional Clustering of Human RAG2 Gene Mutations in Severe Combined Immune Deficiency^*

Barbara Corneo^§¶, Despina Moshous^¶, Isabelle Callebaut^**, Régina de Chasseval, Alain Fischer, and Jean-Pierre de Villartay

From  Développement Normal et Pathologique du Système Immunitaire, INSERM U429, Hôpital Necker Enfants Malades, Paris 75015, France and ^** LMCP, CNRS UMR C7590, Universités Paris 6 et Paris 7, Paris 75005, France

The V(D)J recombination, which leads to the somatic rearrangement of variable, diversity, and joining segments, is the mechanism accountable for the diversity of T cell receptor- and Ig-encoding genes. The products of the RAG1 and RAG2 genes are the lymphoid-specific factors responsible for the initiation of the V(D)J recombination through the generation of a DNA double strand break. RAG1 or RAG2 gene inactivation in the mouse leads to abortion of the V(D)J rearrangement process, early block in both T and B cell maturation, and, ultimately, to severe combined immune deficiency (SCID). A human SCID condition is also characterized by an absence of mature T and B lymphocytes and is associated with mutations in either RAG1- or RAG2-encoding genes. Based on the predicted -propeller three-dimensional structure model for RAG2, we found that six out of the seven mutations described to date in T-B-SCID patients are clustered on one side of the propeller, in regions exposed to solvent. This finding reinforces the biological significance of this predicted model and suggests that RAG1 interacts with RAG2 on one of the side of the scaffold formed by the -propeller.

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^* This work was supported by institutional grants from Institut National de la Santé et de la Recherche Médicale and Ministère de l'Education Nationale de la Recherche et de la Technologie, and grants from Association de Recherche sur le Cancer (ARC), Association contre les myopathies (AFM), and Commissariat à l'Energie Atomique (CEA-LRC 7V).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ Supported by scholarships from the European Community and ARC.

^¶ The first two authors contributed equally to this work.

Supported by scholarships from ARC and the Deutsche Forschungsgemeinschaft.

To whom correspondence should be addressed: INSERM U429, Hôpital Necker, 149 rue de Sevres, 75015 Paris, France. E-mail: devillar@infobiogen.fr.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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