title: Unexpected and variable phenotypes in a family with JAK3 deficiency.
abstract: Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.
authors.affiliation: Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, Bethesda, MD, USA. frucht@cber.fda.gov
authors.forename: D M
authors.initials: DM
authors.lastname: Frucht
authors.forename: M
authors.initials: M
authors.lastname: Gadina
authors.forename: G J
authors.initials: GJ
authors.lastname: Jagadeesh
authors.forename: I
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: K
authors.initials: K
authors.lastname: Takada
authors.forename: J J
authors.initials: JJ
authors.lastname: Bleesing
authors.forename: J
authors.initials: J
authors.lastname: Nelson
authors.forename: L M
authors.initials: LM
authors.lastname: Muul
authors.forename: G
authors.initials: G
authors.lastname: Perham
authors.forename: G
authors.initials: G
authors.lastname: Morgan
authors.forename: E J
authors.initials: EJ
authors.lastname: Gerritsen
authors.forename: R F
authors.initials: RF
authors.lastname: Schumacher
authors.forename: P
authors.initials: P
authors.lastname: Mella
authors.forename: P A
authors.initials: PA
authors.lastname: Veys
authors.forename: T A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: E R
authors.initials: ER
authors.lastname: Kaminski
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: F
authors.initials: F
authors.lastname: Candotti
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism; D002461:Cell Line, Transformed; D002648:Child; D018076:DNA, Complementary; D053222:Fas Ligand Protein; D005260:Female; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3