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 γ-chain (γ(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 γ(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.