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. 2022 Jul;141(7):1279-1286.
doi: 10.1007/s00439-021-02400-1. Epub 2022 Feb 19.

Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

Eline Blommaert  1 , Natalia A Cherepanova  2 , Frederik Staels  3 , Matthew P Wilson  1 , Reid Gilmore  4 , Rik Schrijvers  3 , Jaak Jaeken  5 , François Foulquier  6 , Gert Matthijs  7
Affiliations

Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

Eline Blommaert et al. Hum Genet. 2022 Jul.

Abstract

Mutations in the X-linked gene MAGT1 cause a Congenital Disorder of Glycosylation (CDG), with two distinct clinical phenotypes: a primary immunodeficiency (XMEN disorder) versus intellectual and developmental disability. It was previously established that MAGT1 deficiency abolishes steady-state expression of the immune response protein NKG2D (encoded by KLRK1) in lymphocytes. Here, we show that the reduced steady-state levels of NKG2D are caused by hypoglycosylation of the protein and we pinpoint the exact site that is underglycosylated in MAGT1-deficient patients. Furthermore, we challenge the possibility that supplementation with magnesium restores NKG2D levels and show that the addition of this ion does not significantly improve NKG2D steady-state expression nor does it rescue the hypoglycosylation defect in CRISPR-engineered human cell lines. Moreover, magnesium supplementation of an XMEN patient did not result in restoration of NKG2D expression on the cell surface of lymphocytes. In summary, we demonstrate that in MAGT1-deficient patients, the lack of NKG2D is caused by hypoglycosylation, further elucidating the pathophysiology of XMEN/MAGT1-CDG.

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