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

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 SCID1,2, which is usually(!ly 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,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 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 (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.