MAGT1 messenger RNA-corrected autologous T and natural killer cells for potential cell therapy in X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia disease

Further Delineation of the Spectrum of XMEN Disease in Six Chinese Pediatric Patients

“…Since its first report in 2011, XMEN disease has been reported in a total of 45 patients aged between 18 months and 58 years. All reported patients were detected P/LP variants in the MAGT1 gene (Li et al, 2011;Chaigne-Delalande et al, 2013;Li et al, 2014;Dhalla et al, 2015;Patiroglu et al, 2015;Brigida et al, 2017;He et al, 2018;Blommaert et al, 2019;Dimitrova et al, 2019;Hoyos-Bachiloglu et al, 2020;Klinken et al, 2020;Ravell et al, 2020b;Brault et al, 2021). In total, 30 P/LP variants have been reported, including 3 novel variants identified in this study.…”

“…The most common variant, c.409C > T, appeared in five patients from four unrelated families (Ravell et al, 2020b). Another common variant, c.991C > T, was detected in P4 and P5 from family 4, in two reported patients with classical XMEN (Ravell et al, 2020b;Brault et al, 2021), and in another case with a variable phenotype of developmental disability (Blommaert et al, 2019). Therefore, XMEN appears to exhibit variable severity of clinical phenotypes even with identical genotypes.…”

“…The loss-offunction intolerance (pLI) score MAGT1 is 0.96, and the observed/expected (o/e) ratio is 0.07; suggesting that MAGT1 is highly intolerant to loss-of-function variants. Most reported disease-causing mutations in MAGT1 are loss-of-function variants (Li et al, 2011;Chaigne-Delalande et al, 2013;Li et al, 2014;Dhalla et al, 2015;Patiroglu et al, 2015;Brigida et al, 2017;He et al, 2018;Blommaert et al, 2019;Dimitrova et al, 2019;Ravell et al, 2020b;Hoyos-Bachiloglu et al, 2020;Klinken et al, 2020;Brault et al, 2021). All these novel variants occur upstream to the last MAGT1 exon.…”

“…Considering the unpredictable complications of HSCT and the stable clinical conditions of our six patients, none of them underwent HSCT. Recently, a pre-clinical study demonstrated that ex vivo correcting autologous T and NK cells from XMEN patients through MAGT1 mRNA electroporation can restore NKG2D receptor expression and rescue cytotoxic activity to normal levels (Brault et al, 2021). This highly efficient method avoids genomic integration and the risks of alloimmunity, supporting cell therapy as an attractive immunologic cure for this monogenetic disease.…”

“…Forty-five unique male patients have been reported since XMEN was first reported in 2011 (Li et al, 2011;Chaigne-Delalande et al, 2013;Li et al, 2014;Dhalla et al, 2015;Patiroglu et al, 2015;Brigida et al, 2017;He et al, 2018;Blommaert et al, 2019;Dimitrova et al, 2019;Ravell et al, 2020b;Hoyos-Bachiloglu et al, 2020;Klinken et al, 2020;Brault et al, 2021). However, only two cases from one family have been reported in China to date.…”