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Illig, David; Navratil, Marta; Kelecic, Jadranka; Conca, Raffaele; Hojsak, Iva; Jadresin, Oleg; Coric, Marijana; Vukovic, Jurica; Rohlfs, Meino; Hollizeck, Sebastian; Bohne, Jens; Klein, Christoph and Kotlarz, Daniel (2019): Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency. In: Journal of Clinical Immunology, Vol. 39, No. 2: pp. 207-215

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Inborn errors in interleukin 2 receptor, gamma (IL2RG) perturb signaling of the common gamma chain family cytokines and cause severe combined immunodeficiency (SCID). Here, we report two brothers suffering from chronic cryptosporidiosis, severe diarrhea, and cholangitis. Pan T, B, and NK cell numbers were normal, but immunophenotyping revealed defective B cell differentiation. Using whole exome sequencing, we identified a base pair deletion in the first exon of IL2RG predicted to cause a frameshift and premature stop. However, flow cytometry revealed normal surface expression of the IL-2R chain. While IL-2, IL-7, and IL-15 signaling showed only mild defects of STAT5 phosphorylation in response to the respective cytokines, IL-4- and IL-21-induced phosphorylation of STAT3 and STAT6 was markedly reduced. Examination of RNA isoforms detected alternative splicing downstream of IL2RG exon 1 in both patients resulting in resolution of the predicted frameshift and 16 mutated amino acids. In silico modeling suggested that the IL-2R mutation reduces the stabilization of IL-4 and IL-21 cytokine binding by affecting the N-terminal domain of the IL-2R. Thus, our study shows that IL2RG deficiency can be associated with differential signaling defects. Confounding effects of alternative splicing may partially rescue genetic defects and should be considered in patients with inborn errors of immunity.

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