title: Impaired IL-7 signaling may explain a case of atypical JAK3-SCID.
abstract: Janus kinase 3-severe combined immunodeficiency (JAK3-SCID) is an autosomal recessive immunodeficiency disease caused by various mutations in the JAK3 gene. Typical JAK3-SCID is characterized by a phenotype in which B cells are present but T and NK cells are not, the T(-)B(+)NK(-) phenotype, and by impaired signaling through cytokine receptors that use the common gamma chain (gammac) subunit. An atypical JAK3-SCID case carrying a single glutamate to glycine substitution mutation (E481G) in the JH3 domain of one JAK3 allele, and a deletion mutation (del482-596) in the JH3 and JH2 domains of the other allele was reported previously. Although this patient had CD4(+) T cells and NK cells unlike typical cases, the CD4(+) T cells were functionally impaired. We report here that the JAK3-E481G mutant transduced IL-2-, IL-4-, IL-15-, and IL-21-induced signals as efficiently as wild-type JAK3. However, this mutant failed to respond to IL-7 by phosphorylating JAK1, JAK3, or STAT5. The other mutant JAK3, JAK3-del482-596, was non-functional. Thus, an impaired IL-7 signal may cause SCID and compromise T-cell differentiation, even if the IL-15 signal is preserved and supports NK-cell development, as in this patient.
authors.affiliation: Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. rikun@immunol.med.kindai.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nara
authors.forename: Mizanur
authors.initials: M
authors.lastname: Rahman
authors.forename: Farha Matin
authors.initials: FM
authors.lastname: Juliana
authors.forename: Akemi
authors.initials: A
authors.lastname: Araki
authors.forename: Hironobu
authors.initials: H
authors.lastname: Asao
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D017354:Point Mutation; D053655:Receptors, Interleukin-21 / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D000098546:Interleukin-21
chemical_list: D019409:Interleukin-15; D015851:Interleukin-7; D007378:Interleukins; D053655:Receptors, Interleukin-21; D019948:Receptors, Interleukin-4; D020395:Receptors, Interleukin-7; D015847:Interleukin-4; D053616:Janus Kinase 3; D000098546:Interleukin-21