Functional characterization of a novel IL2RG mutation causing atypical SCID

Abstract

The interleukin-2 receptor common gamma chain gene (IL2RG) encodes for the common gamma chain (yc), which is a part of multiple interleukin receptors such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptor. T cell proliferation and cytokine production is induced due to its activation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription 5 (STAT5) depended signaling pathway. Therefore, mutations in this gene can cause impaired cell-mediated and humoral immunity leading to severe combined immunodeficiency (SCID). From birth patients suffer from total absent or greatly reduced T and NK cells being susceptible to opportunistic pathogens, which shows in recurrent respiratory and viral infections. Usually, the infants die within the first year of life unless undergoing prompt hematopoietic stem cell transplantation or gene therapy. Lately, hypomorphic mutations in the IL2RG gene with milder phenotypes have been described. Unlike SCID, the cells of the lymphatic lineage can be detected in peripheral blood count even if they display functional impairment. This work focuses on the functional characterization of a novel c.458T>C; p.Ile153Thr IL2RG missense-mutation observed in three brothers. They were diagnosed with atypical SCID due to their milder phenotype expression. Functional characterization of the common gamma chain (γc) revealed its hypomorphic function. In addition, we detected somatic reversion predominantly in lymphoid derived subpopulations. The combination of hypomorphic IL2RG function and somatic reversion explains the atypical phenotype of the patients and serves as a model for novel gene editing tools (e.g., CRISPR/Cas9) imitating the process of natural gene therapy.