title: A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency.
abstract: X-linked severe combined immunodeficiency is caused by mutations in the IL-2 receptor common gamma chain and classically presents in the first 6 months of life with predisposition to bacterial, viral and fungal infections. In most instances, affected individuals are lymphopenic with near complete absence of T cells and NK cells. We report a boy who presented at 12 months of age with Pneumocystis jiroveci pneumonia and a family history consistent with X-linked recessive inheritance. He had a normal lymphocyte count including the presence of T cells and a broad T-cell-receptor diversity, as well as normal surface expression of the common gamma chain (CD132) protein. He however had profound hypogammaglobulinaemia, and IL-2-induced STAT5 phosphorylation was absent. Sequencing of IL-2RG demonstrated a 12-base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL2RG mRNA species. A review of the literature identified 4 other patients with T-cell-positive X-SCID, with the current patient being the first associated with an mRNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT5 phosphorylation might nonetheless support T-cell development. Possible explanations are that STAT5-mediated signal transduction may be less relevant to IL7-receptor-mediated T-cell development than are other IL7R-induced intracellular transduction pathways or that a low level of STAT5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T-cell development.
authors.affiliation: Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
authors.forename: P E A
authors.initials: PE
authors.lastname: Gray
authors.forename: G J
authors.initials: GJ
authors.lastname: Logan
authors.forename: I E
authors.initials: IE
authors.lastname: Alexander
authors.forename: S
authors.initials: S
authors.lastname: Poulton
authors.forename: T
authors.initials: T
authors.lastname: Roscioli
authors.forename: J
authors.initials: J
authors.lastname: Ziegler
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics*; D018655:Lymphocyte Count; D008297:Male; D010766:Phosphorylation / Q000235:genetics; D045363:Pneumocystis carinii / Q000276:immunology / Q000472:pathogenicity; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000276:immunology
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor