title: Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U132, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: J P
authors.initials: JP
authors.lastname: DiSanto
authors.forename: F
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: A
authors.initials: A
authors.lastname: Dautry-Varsat
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology*; D014960:X Chromosome
chemical_list: D017931:DNA Primers; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2