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

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 1 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 Janus kinase 3 (JAK3)-dependent interleukin-2 (IL-2)-induced signal transducer and activator of transcription-5 (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, whereas 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. Natural killer (NK) function was severely depressed at presentation in the 4 patients studied, whereas after transplantation 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.