IMPAIRMENT OF LIGAND-BINDING AND GROWTH SIGNALING OF MUTANT IL-2 RECEPTOR GAMMA-CHAINS IN PATIENTS WITH X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

The IL-2R gamma-chain is an indispensable subunit for the functional I L-2R. Recently, mutations of the gamma-chain have been reported to be closely associated with X-linked severe combined immunodeficiency (XSC ID). The present study reveals that three patients with XSCID have thr ee different mutations in the gamma-chain; a point mutation, a two con secutive-base deletion, and lack of the second exon in mRNA. The point mutation that we have detected is C to T, which results in one amino acid substitution of valine for alanine in the extracellular domain of the IL-2R gamma-chain (named AV mutant). The two-base deletion detect ed causes a frame shift of the coding region in the SH2 subdomain in t he cytoplasmic domain (named tSH mutant). Transfection studies perform ed with the mutant gamma-chains demonstrated that the AV mutant and tS H mutant failed to bind to IL-2 and to transduce growth signals, respe ctively. These findings indicate that the gamma-chain gene mutations t hat accompany XSCID induce loss of the gamma-chain function, possibly resulting in stagnation of the differentiation and development of T ce lls.