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izvor podataka: crosbi

Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency (CROSBI ID 263918)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Illig, David ; Navratil, Marta ; Kelečić, Jadranka ; Conca, Raffaele ; Hojsak, Iva ; Jadrešin, Oleg ; Ćorić, Marijana ; Vuković, Jurica ; Rohlfs, Meino ; Hollizeck, Sebastian et al. Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency // Journal of clinical immunology, 39 (2019), 2; 207-215. doi: 10.1007/s10875-019-00606-7

Podaci o odgovornosti

Illig, David ; Navratil, Marta ; Kelečić, Jadranka ; Conca, Raffaele ; Hojsak, Iva ; Jadrešin, Oleg ; Ćorić, Marijana ; Vuković, Jurica ; Rohlfs, Meino ; Hollizeck, Sebastian ; Bohne, Jens ; Klein, Christoph ; Kotlarz, Daniel

engleski

Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency

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.

IL21

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

Podaci o izdanju

39 (2)

2019.

207-215

objavljeno

0271-9142

1573-2592

10.1007/s10875-019-00606-7

Povezanost rada

Kliničke medicinske znanosti

Poveznice
Indeksiranost