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

Blood. 2004 Mar 15;103(6):2009-18. doi: 10.1182/blood-2003-06-2104. Epub 2003 Nov 13.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Line, Transformed
  • Codon, Nonsense
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Deletion
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Infant
  • Interleukin-2 / pharmacology
  • Janus Kinase 3
  • Killer Cells, Natural / immunology
  • Male
  • Milk Proteins*
  • Mutation, Missense*
  • Phenotype
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT5 Transcription Factor
  • Severe Combined Immunodeficiency / genetics*
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / therapy*
  • Trans-Activators / metabolism
  • United States


  • Codon, Nonsense
  • DNA-Binding Proteins
  • Interleukin-2
  • Milk Proteins
  • STAT5 Transcription Factor
  • Trans-Activators
  • Protein-Tyrosine Kinases
  • JAK3 protein, human
  • Janus Kinase 3