analyses of 10 patients and outcomes of stem cell transplantation Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular

AbstractWe 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.From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.