Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency

Show full item record



Permalink

http://hdl.handle.net/10138/317341

Citation

Tuovinen , E A , Grönholm , J , Öhman , T , Pöysti , S , Toivonen , R , Kreutzman , A , Heiskanen , K , Trotta , L , Toiviainen-Salo , S , Routes , J M , Verbsky , J , Mustjoki , S , Saarela , J , Kere , J , Varjosalo , M , Hänninen , A & Seppänen , M R J 2020 , ' Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency ' , Journal of Clinical Immunology , vol. 40 , no. 3 , pp. 503-514 . https://doi.org/10.1007/s10875-020-00745-2

Title: Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency
Author: Tuovinen, Elina A.; Grönholm, Juha; Öhman, Tiina; Pöysti, Sakari; Toivonen, Raine; Kreutzman, Anna; Heiskanen, Kaarina; Trotta, Luca; Toiviainen-Salo, Sanna; Routes, John M.; Verbsky, James; Mustjoki, Satu; Saarela, Janna; Kere, Juha; Varjosalo, Markku; Hänninen, Arno; Seppänen, Mikko R. J.
Contributor: University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Institute of Biotechnology
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, HUS Children and Adolescents
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUS Medical Imaging Center
University of Helsinki, HUS Comprehensive Cancer Center
University of Helsinki, HUSLAB
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Molecular Systems Biology
University of Helsinki, Children's Hospital
Date: 2020-04
Language: eng
Number of pages: 12
Belongs to series: Journal of Clinical Immunology
ISSN: 0271-9142
URI: http://hdl.handle.net/10138/317341
Abstract: Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.
Subject: X-linked combined immunodeficiency diseases
severe combined immunodeficiency
atypical
interleukin receptor common gamma subunit
IL2RG
endoplasmic reticulum
Golgi apparatus
COMBINED IMMUNE-DEFICIENCY
GAMMA-CHAIN
CELL DIFFERENTIATION
INTERLEUKIN-2 IL-2
T-LYMPHOCYTES
NK-CELLS
REVERSION
BIOLOGY
DISEASE
PROLIFERATION
3111 Biomedicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Tuovinen2020_Ar ... izygousIL2RGPPro58SerM.pdf 1.693Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record