Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID)

• Published in: Nature (London) 1995-09, Vol.377 (6544), p.65-68
• Main Authors: Macchi, Paolo, Villa, Anna, Giliani, Silvia, Sacco, Maria G, Frattini, Annalisa, Porta, Fulvio, Ugazio, Alberto G, Johnston, James A, Candotti, Fabio, O'Sheai, John J, Vezzoni, Paolo, Notarangelo, Luigi D
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - immunology; Base Sequence; Biological and medical sciences; Cell Line, Transformed; Chromosomes; DNA Mutational Analysis; DNA Primers; Genes; Genetics; Humanities and Social Sciences; Humans; Immunity (Disease); Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Jak3 gene; Janus Kinase 3; letter; Lymphocytes; man; Medical sciences; Molecular Sequence Data; multidisciplinary; Mutation; Polymerase Chain Reaction; protein kinase; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Science; Science (multidisciplinary); Sequence Deletion; severe combined immunodeficiency; Severe Combined Immunodeficiency - enzymology; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; T-Lymphocytes - immunology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/377065a0

SEVERE combined immune deficiency (SCID) represents a hetero-genous group of hereditary diseases. Mutations in the common γ-chain (γ c ), which is part of several cytokine receptors including those for interleukin (IL)-2, IL-4, IL-7, IL-9 and FL-15, are responsible for X-linked SCID 1,2 , 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 3,4 has been found to associate with the γ c -chain-containing cytokine receptors 4–9 . Therefore Jak-3 or other STAT proteins with which it interacts 10,11 are candidate genes for autosomal recessive T - B + SCID7. 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 (TyrlOO→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.