Sarah M. Russell,  Nahid Tayebi (1),  Hiroshi Nakajima (1),  Mary C. Riedy (2),  Joseph L. Roberts (2),  M. Javad Aman (2),  Thi-Sau Migone,  Masayuki Noguchi,  M. Louise Markert,  Rebecca H. Buckley,  John J. O'Shea,  Warren J. Leonard (3)

Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor chain () 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 , 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 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 signaling, 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 are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

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.
(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.