ORIGINAL ARTICLE Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency David Illig 1 & Marta Navratil 2,3 & Jadranka Kelečić 4 & Raffaele Conca 1 & Iva Hojsak 3,5,6 & Oleg Jadrešin 5 & Marijana Ćorić 7 & Jurica Vuković 8 & Meino Rohlfs 1 & Sebastian Hollizeck 1 & Jens Bohne 9 & Christoph Klein 1 & Daniel Kotlarz 1 Received: 12 December 2018 /Accepted: 25 February 2019 /Published online: 21 March 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract 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-2Rγ 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-2Rγ mutation reduces the stabilization of IL-4 and IL-21 cytokine binding by affecting the N-terminal domain of the IL-2Rγ. 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. Keywords SCID . immunodeficiency . IL-21R . IL-2R . splicing Introduction Severe combined immunodeficiency (SCID) is a rare disease characterized by the absence of functional T cells and can be immunologically sub-grouped based on the presence or ab- sence of B and NK cells (T - B + NK + ,T - B - NK + ,T - B + NK - , and T - B - NK - forms) [1]. Clinically, SCID often manifests with failure to thrive and recurrent infections of the respiratory Christoph Klein and Daniel Kotlarz contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00606-7) contains supplementary material, which is available to authorized users. * Daniel Kotlarz daniel.kotlarz@med.uni-muenchen.de 1 Dr. von Hauner Children’ s Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337 Munich, Germany 2 Department of Pulmonology, Allergology, Rheumatology and Clinical Immunology, Children’ s Hospital Zagreb, Zagreb, Croatia 3 School of Medicine, University J.J. Strossmayer, Osijek, Croatia 4 Department of Pediatrics, Division of Clinical Immunology, Allergology, Respiratory Diseases and Rheumatology, University Hospital Centre Zagreb, Kišpatićeva 12, Zagreb 10000, Croatia 5 Referral Center for Pediatric Gastroenterology and Nutrition, Children’ s Hospital Zagreb, Zagreb, Croatia 6 School of Medicine, University of Zagreb, Zagreb, Croatia 7 Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia 8 Division of Pediatric Gastroenterology, Hepatology and Nutrition, University Hospital Centre Zagreb, Zagreb, Croatia 9 Institute for Virology, Hannover Medical School, Hannover, Germany Journal of Clinical Immunology (2019) 39:207–215 https://doi.org/10.1007/s10875-019-00606-7