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

Abstract

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.