X chromosome-linked severe combined immunodeficiency disease (SCIDX1) is characterized by the absence of T-cell and natural killer cell development and results from molecular mutations of the interleukin 2 receptor (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 severe immunophenotype in SCIDX1. We have previously described an atypical SCIDX1 syndrome demonstrating poorly functioning peripheral T cells, which we hypothesized to represent a variant allele at the SCIDX1 locus. We now demonstrate that a splice site mutation in the IL-2R gamma gene is responsible for this atypical SCIDX1. Aberrant RNA splicing resulted in the generation of two IL-2R gamma transcripts: an abundant, nonfunctional isoform containing a small intronic insertion and a second functional isoform with a single amino acid substitution present in limited amounts. Radiolabeled IL-2 binding studies revealed a 5-fold decreased level of expression of functional high-affinity IL-2Rs, which correlated with the quantity of full-length IL-2R gamma transcripts. Further analysis of the T-cell antigen receptor beta-chain repertoire of the patient's T cells demonstrated oligoclonality in multiple V beta families, thus strongly suggesting that the defect in the IL-2R gamma chain generated a limited number of peripheral T-cell clones. This atypical SCIDX1 patient demonstrates that certain IL-2R gamma chain abnormalities can also result in partial immunodeficiency phenotypes, potentially through differential effects on the IL-2, IL-4, or IL-7 receptor systems
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