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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 S evere combined immunodeficiency
Author(s) -
Gray P. E. A.,
Logan G. J.,
Alexander I. E.,
Poulton S.,
Roscioli T.,
Ziegler J.
Publication year - 2015
Publication title -
international journal of immunogenetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.41
H-Index - 47
eISSN - 1744-313X
pISSN - 1744-3121
DOI - 10.1111/iji.12166
Subject(s) - biology , signal transduction , phosphorylation , rna splicing , receptor , t cell , gene , exon , alternative splicing , common gamma chain , genetics , microbiology and biotechnology , rna , immune system , interleukin 21 receptor
Summary 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 P neumocystis 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 ( CD 132) protein. He however had profound hypogammaglobulinaemia, and IL ‐2‐induced STAT 5 phosphorylation was absent. Sequencing of IL ‐2 RG demonstrated a 12‐base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL 2 RG m RNA 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 m RNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT 5 phosphorylation might nonetheless support T ‐cell development. Possible explanations are that STAT 5‐mediated signal transduction may be less relevant to IL 7‐receptor‐mediated T ‐cell development than are other IL 7 R ‐induced intracellular transduction pathways or that a low level of STAT 5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T ‐cell development.