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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2009-2018.
Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-06-2104.
Submitted June 25, 2003
Accepted October 22, 2003
Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation
Joseph L Roberts*, Andrea Lengi, Stephanie M Brown, Min Chen, Yong-Jie Zhou, John J O'Shea, and Rebecca H Buckley
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: rober060{at}mc.duke.edu.
We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With the exception of one individual with persistence of transplacentally-transferred maternal lymphocytes, all infants presented with a T-B+NK- phenotype. The patient mutations all resulted in abnormal B cell JAK3-dependent IL-2-induced STAT5 phosphorylation. Additional analyses of mutations permitting protein expression revealed the N-terminal JH7 (Del58A) and JH6 (D169E) domain mutations each inhibited receptor binding and catalytic activity, while the G589S JH2 mutation abrogated kinase activity but did not affect  c association. Nine of the 10 patients are currently alive from between 4 years and 18 years following stem cell transplantation, with all exhibiting normal T cell function. Reconstitution of antibody function was noted in only 3 patients. NK function was severely depressed at presentation in the 4 patients studied while post-transplant the only individuals with normal NK lytic activity were patients 1 and 5. Hence, bone marrow transplantation is an effective means for reconstitution of T cell immunity in this defect but is less successful for restoration of B cell and NK cell functions.
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