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Science 4 October 1996:
Vol. 274. no. 5284, pp. 97 - 99
DOI: 10.1126/science.274.5284.97
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Reports

RAG Mutations in Human B Cell-Negative SCID

Klaus Schwarz, * George H. Gauss, Leopold Ludwig, Ulrich Pannicke, Zhong Li, Doris Lindner, Wilhelm Friedrich, Reinhard A. Seger, Thomas E. Hansen-Hagge, Stephen Desiderio, Michael R. Lieber, Claus R. Bartram dagger

Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B+ SCID) and those without (B- SCID). Although several genetic causes are known for B+ SCID, the etiology of B- SCID has not been defined. Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both. This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease.

K. Schwarz and C. R. Bartram, Section of Molecular Biology and Department of Pediatrics II, University of Ulm, D-89070 Ulm, Germany.
G. H. Gauss and M. R. Lieber, Department of Pathology, School of Medicine, Washington University, St. Louis, MO 63110, USA.
L. Ludwig, Department of Internal Medicine I, University of Ulm, D-89070 Ulm, Germany.
U. Pannicke, D. Lindner, T. E. Hansen-Hagge, Section of Molecular Biology, University of Ulm, D-89070 Ulm, Germany.
Z. Li and S. Desiderio, Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
W. Friedrich, Department of Pediatrics II, University of Ulm, D-89070 Ulm, Germany.
R. A. Seger, University Children's Hospital, University of Zürich, Zürich, Switzerland.
*   To whom correspondence should be addressed at the Department of Transfusion Medicine, University of Ulm, Helmholtzstrabeta e 10, D-89081 Germany. E-mail: klaus.schwarz{at}medizin.uni-ulm.de

dagger    Present address: Institute of Human Genetics, University of Heidelberg, D-69120 Heidelberg, Germany.

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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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