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Abstract

Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor γ chain (γc) gene that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with γc, so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype. A girl with immunological features indistinguishable from those of XSCID was therefore selected for analysis. An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal γc expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA. Sequencing revealed a different mutation on each allele: a single nucleotide insertion resulting in a frame shift and premature termination in the Jak3 JH4 domain and a nonsense mutation in the Jak3 JH2 domain. The lack of Jak3 expression correlated with impaired B cell signacrcling, as demonstrated by the inability of IL-4 to activate Stat6 in the EBV-transformed cell line from the patient. These observations indicate that the functions of γc are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

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Science
Volume 270 | Issue 5237
3 November 1995

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Published in print: 3 November 1995

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Sarah M. Russell
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Nahid Tayebi(1)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Hiroshi Nakajima(1)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Mary C. Riedy(2)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Joseph L. Roberts(2)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
M. Javad Aman(2)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Thi-Sau Migone
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Masayuki Noguchi
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
M. Louise Markert
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Rebecca H. Buckley
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
John J. O'Shea
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Warren J. Leonard(3)
S. M. Russell, H. Nakajima, M. J. Aman, T.-S. Migone, M. Noguchi, W. J. Leonard, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
N. Tayebi, Unit on Clinical Genetics, Clinical Neuroscience Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
M. C. Riedy and J. J. O'Shea, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
J. L. Roberts, Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
M. L. Markert and R. H. Buckley, Departments of Immunology and Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.

Notes

(1)
These authors contributed equally to this work.
(2)
These authors contributed equally to this work.
(3)
To whom correspondence should be addressed at Laboratory of Molecular Immunology, NHLBI, NIH, Building 10, Room 7N244, Bethesda, MD 20892-1674, USA.

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