Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency
| Autor: | Christoph Klein, Daniel Kotlarz, Jens Bohne, Jadranka Kelecic, David Illig, Marta Navratil, Sebastian Hollizeck, Marijana Ćorić, Raffaele Conca, Jurica Vuković, Iva Hojsak, Oleg Jadrešin, Meino Rohlfs |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Diarrhea Male Cholangitis Croatia Immunology Cryptosporidiosis Biology medicine.disease_cause Frameshift mutation 03 medical and health sciences Exon 0302 clinical medicine medicine Immunology and Allergy Humans Cytokine binding Respiratory Tract Infections IL21 Common gamma chain Severe combined immunodeficiency Mutation B-Lymphocytes Alternative splicing Interleukin-21 Receptor alpha Subunit medicine.disease Molecular biology Alternative Splicing 030104 developmental biology Child Preschool RNA splicing Severe Combined Immunodeficiency 030215 immunology |
| Zdroj: | Journal of clinical immunology. 39(2) |
| ISSN: | 1573-2592 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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