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

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.