MUTATIONS OF JAK-3 GENE IN PATIENTS WITH AUTOSOMAL SEVERE COMBINED IMMUNE-DEFICIENCY (SCID)

SEVERE combined immune deficiency (SCID) represents a heterogenous gro up of hereditary diseases. Mutations in the common gamma-chain (gamma( c)), which is part of several cytokine receptors including those for i nterleukin (IL)-2, IL-4, IL-7, IL-9 and IL-15, are responsible for X-l inked SCID1,2, which is usually(!ly associated with a lack of circulat ing 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,vith the gamma( c)-chain-containing cytokine receptors(4-9). Therefore Jak-3 or other STAT proteins with which it interacts(10,11) are candidate genes for a utosomal 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 (Tyr1 00-->Cys) in a conserved tyrosine residue in the JH7 domain of Jak-3 w hich is absent in more than 150 investigated chromosomes. The other pa tient carries a homozygous 151-base-pair deletion in the kinase-like d omain, leading to a frameshift and premature termination. Both mutatio ns resulted in markedly reduced levels of Jak-3, These findings show t hat abnormalities in the Jak/STAT signalling pathway can account for S CID in humans.