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Tytuł pozycji:

Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder

Tytuł :
Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder
Autorzy :
Beibei Wu
Laura Rice
Jennifer Shrimpton
Dylan Lawless
Kieran Walker
Clive Carter
Lynn McKeown
Rashida Anwar
Gina M Doody
Sonal Srikanth
Yousang Gwack
Sinisa Savic
Pokaż więcej
Temat :
immunodeficiency
CRACR2A
T cells
Medicine
Science
Biology (General)
QH301-705.5
Źródło :
eLife, Vol 10 (2021)
Wydawca :
eLife Sciences Publications Ltd, 2021.
Rok publikacji :
2021
Kolekcja :
LCC:Medicine
LCC:Science
LCC:Biology (General)
Typ dokumentu :
article
Opis pliku :
electronic resource
Język :
English
ISSN :
2050-084X
Relacje :
https://elifesciences.org/articles/72559; https://doaj.org/toc/2050-084X
DOI :
10.7554/eLife.72559
Dostęp URL :
https://doaj.org/article/3bc52deffd5148cea866655819e240e0
Numer akcesji :
edsdoj.3bc52deffd5148cea866655819e240e0
Czasopismo naukowe
CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca2+-NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in CRACR2A [paternal allele c.834 gaG> gaT (p.E278D) and maternal alelle c.430 Aga > Gga (p.R144G) c.898 Gag> Tag (p.E300*)], the gene encoding CRACR2A. The 33-year-old patient of East-Asian origin exhibited late onset combined immunodeficiency characterised by recurrent chest infections, panhypogammaglobulinemia and CD4+ T cell lymphopenia. In vitro exposure of patient B cells to a T-dependent stimulus resulted in normal generation of antibody-secreting cells, however the patient’s T cells showed pronounced reduction in CRACR2A protein levels and reduced proximal TCR signaling, including dampened SOCE and reduced JNK phosphorylation, that contributed to a defect in proliferation and cytokine production. Expression of individual allelic mutants in CRACR2A-deleted T cells showed that the CRACR2AE278D mutant did not affect JNK phosphorylation, but impaired SOCE which resulted in reduced cytokine production. The truncated double mutant CRACR2AR144G/E300* showed a pronounced defect in JNK phosphorylation as well as SOCE and strong impairment in cytokine production. Thus, we have identified variants in CRACR2A that led to late-stage combined immunodeficiency characterized by loss of function in T cells.

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