MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.

BACKGROUND: X-Linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for the magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a Congenital Disorder of Glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and responsible for life-threatening bleeding events have never been investigated.

OBJECTIVES: To assess platelet functions in XMEN patients.

PATIENTS/METHODS: Two unrelated young boys, including one before and after hematopoietic stem-cell transplantation (HSCT), were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans.

RESULTS: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIb β3 activation, calcium mobilization and protein kinase C (PKC) activity were impaired in both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide (PAR1-AP) were absent at both low and high concentrations. These defects were also associated with decreased molecular weight of glycoprotein (GP)Ibα, GPVI and integrin αIIb due to a partial impairment of N-glycosylation. All these defects were corrected after HSCT.

CONCLUSIONS: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and a defective N-glycosylation in several platelet proteins, that could explain the hemorrhages reported in XMEN patients.