title: Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.
abstract: 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.
authors: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. rober060@mc.duke.edu
authors: Joseph L
authors: JL
authors: Roberts
authors: Andrea
authors: A
authors: Lengi
authors: Stephanie M
authors: SM
authors: Brown
authors: Min
authors: M
authors: Chen
authors: Yong-Jie
authors: YJ
authors: Zhou
authors: John J
authors: JJ
authors: O'Shea
authors: Rebecca H
authors: RH
authors: Buckley
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000494:pharmacology; D053616:Janus Kinase 3; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008894:Milk Proteins; D020125:Mutation, Missense; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D015534:Trans-Activators / Q000378:metabolism; D014481:United States
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3