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A RAG1 Mutation Found in Omenn Syndrome Causes Coding Flank Hypersensitivity: A Novel Mechanism for Antigen Receptor Repertoire Restriction¹

Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, and Department of Pathology, New York University School of Medicine, New York, NY 10016

Hypomorphic RAG mutants with severely reduced V(D)J recombination activity cause Omenn Syndrome (OS), an immunodeficiency with features of immune dysregulation and a restricted TCR repertoire. Precisely how RAG mutants produce autoimmune and allergic symptoms has been unclear. Current models posit that the severe recombination defect restricts the number of lymphocyte clones, a few of which are selected upon Ag exposure. We show that murine RAG1 R972Q, corresponding to an OS mutation, renders the recombinase hypersensitive to selected coding sequences at the hairpin formation step. Other RAG1 OS mutants tested do not manifest this sequence sensitivity. These new data support a novel mechanism for OS: by selectively impairing recombination at certain coding flanks, a RAG mutant can cause primary repertoire restriction, as opposed to a more random, limited repertoire that develops secondary to severely diminished recombination activity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant AI36420 (to D.B.R.) and by the Irene Diamond Foundation (to D.B.R.).

² S.-Y.W. and C.P.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. David B. Roth, Department of Pathology, New York University School of Medicine, 540 First Avenue, New York, NY 10016. E-mail address: roth{at}saturn.med.nyu.edu

⁴ Abbreviations used in this paper: OS, Omenn syndrome; CHO, Chinese hamster ovary; RSS, recombination signal sequence.

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The JI 2008 181: 3729-3730. [Full Text]