DEFECTIVE HUMAN INTERLEUKIN-2 RECEPTOR-GAMMA CHAIN IN AN ATYPICAL X-CHROMOSOME-LINKED SEVERE COMBINED IMMUNODEFICIENCY WITH PERIPHERAL T-CELLS

X chromosome-linked severe combined immunodeficiency disease (SCIDX1) is characterized by the absence of T-cell and natural killer cell deve lopment and results from molecular mutations of the interleukin 2 rece ptor (IL-2R) gamma chain. The IL-2R gamma chain is a common component of the IL-2, IL-4, and IL-7 receptor systems, which may explain the se vere immunophenotype in SCIDX1. We have previously described an atypic al SCIDX1 syndrome demonstrating poorly functioning peripheral T cells , which we hypothesized to represent a variant allele at the SCIDX1 lo cus. We now demonstrate that a splice site mutation in the IL-2R gamma gene is responsible for this atypical SCIDX1. Aberrant RNA splicing r esulted in the generation of two IL-2R gamma transcripts: an abundant, nonfunctional isoform containing a small intronic insertion and a sec ond functional isoform with a single amino acid substitution present i n limited amounts. Radiolabeled IL-2 binding studies revealed a 5-fold decreased level of expression of functional high-affinity IL-2Rs, whi ch correlated with the quantity of full-length IL-2R gamma transcripts . Further analysis of the T-cell antigen receptor beta-chain repertoir e of the patient's T cells demonstrated oligoclonality in multiple V-b eta families, thus strongly suggesting that the defect in the IL-2R ga mma chain generated a limited number of peripheral T-cell clones. This atypical SCIDX1 patient demonstrates that certain IL-2R gamma chain a bnormalities can also result in partial immunodeficiency phenotypes, p otentially through differential effects on the IL-2, IL-4, or IL-7 rec eptor systems.