The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype

Abstract

Summary In addition to their detection in typical X‐linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)‐2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4‐year‐old boy with lethal Epstein–Barr virus‐related lymphoma and his asymptomatic 8‐month‐old brother with a TlowB+natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL‐2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription‐1 (STAT‐5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc), which showed partially preserved function. Co‐immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc. Here, we describe how the R328X mutation in IL‐2RG may allow partial phosphorylation of STAT‐5 through a JAK3‐independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

A great disturbance in the force: IL-2 receptor defects disrupt immune homeostasis

“…Consistent with chronic inflammation, many of IL-2Rα and IL-2Rβ deficient patients presented with elevated IgG with variable vaccine responses [8,59,60,63,64,66–68]. Some patients with atypical X-SCID may also present with dysgammaglobulinemia and elevated IgG [69].…”

“…Although these may include some classic opportunistic infections such as candidiasis, no IL-2Rα or IL-2Rβ, deficiencies presented with PJP pneumonia, and IL-2Rγ patients with atypical phenotypes presented with PJP less frequently than patients with typical X-SCID [21,55 ▪ ]. IL-2Rα, IL-2Rβ, and atypical IL-2Rγ patients presented with prominent viral infections, including severe respiratory viral infections, but most notably CMV and other herpesvirus infections [21,55 ▪ ,69]. Strikingly, all of the IL-2Rα or IL-2Rβ patients that survived the neonatal period developed herpesvirus infections, with 5/7 IL-2Rβ and 5/5 IL-2Rβ patients developing CMV disease [8,55 ▪ ,59,60,62,64–68].…”

“…HSCT of five IL-2Rb deficient patients have been reported, one patient died from multiorgan failure following graft failure and persistent inflammation and one patient died from respiratory failure, presumably from CMV [59,60,68]. Transplantation of atypical X-SCID patients requires cytoreductive conditioning [27,33,56,69], in one case the transplant had to be repeated after initial transplant without conditioning resulted in graft failure.…”

A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair

“…This wide variety of immunological subtypes, caused by a continuously increasing repertoire of SCID-associated genes and variants, results in a highly heterogeneous spectrum of SCID diseases (9). Hypomorphic mutations, categorized as 'leaky SCID', cause a milder phenotype with often a later onset of disease and also contribute to the complexity of these distinct immunological phenotypes (10)(11)(12)(13)(14)(15). Currently, allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice but the genetic subtype greatly impacts long-term survival and immune reconstitution (16).…”