title: Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).
abstract: Severe combined immune deficiency (SCID) represents a heterogenous group of hereditary diseases. Mutations in the common gamma-chain (gamma c), which is part of several cytokine receptors including those for interleukin (IL)-2, IL-4, IL-7, IL-9 and IL-15, are responsible for X-linked SCID, which is usually associated with a lack of circulating T cells and the presence of B lymphocytes (T- B+ SCID). The gene(s) responsible for autosomal recessive T- B+ SCID is still unknown. The Jak-3 protein kinase has been found to associate with the gamma c-chain-containing cytokine receptors. Therefore Jak-3 or other STAT proteins with which it interacts are candidate genes for autosomal recessive T- B+ SCID. Here we investigate two unrelated T- B+ SCID patients (both from consanguineous parents) who have homozygous mutations in the gene for Jak-3. One patient carries a mutation (Tyr100-->Cys) in a conserved tyrosine residue in the JH7 domain of Jak-3 which is absent in more than 150 investigated chromosomes. The other patient carries a homozygous 151-base-pair deletion in the kinase-like domain, leading to a frameshift and premature termination. Both mutations resulted in markedly reduced levels of Jak-3. These findings show that abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.
authors.affiliation: Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Macchi
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: M G
authors.initials: MG
authors.lastname: Sacco
authors.forename: A
authors.initials: A
authors.lastname: Frattini
authors.forename: F
authors.initials: F
authors.lastname: Porta
authors.forename: A G
authors.initials: AG
authors.lastname: Ugazio
authors.forename: J A
authors.initials: JA
authors.lastname: Johnston
authors.forename: F
authors.initials: F
authors.lastname: Candotti
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis; D017931:DNA Primers; D006801:Humans; D053616:Janus Kinase 3; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D017931:DNA Primers; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3