Structural divergence of G6PD variants shapes red blood cell storage and transfusion performance
Issaian, A. V.; Bevers, S.; Marsh, E.; Karafin, M. S.; Schlimgen, R. R.; Reisz, J. A.; Hay, A.; Keele, G. R.; Dzieciatkowska, M.; Cendali, F. I.; Haiman, Z. B.; Key, A. M.; Nemkov, T.; Stephenson, D.; Moore, A.; Palha, M. S.; Legenzov, E. A.; Lamb, D. R.; Deng, X.; Stone, M.; Hansen, K.; Kleinman, S.; Norris, P. J.; Busch, M. P.; Vallese, F.; Hartwick, E. W.; Jung, J.; Palsson, B. O.; Spitalnik, S.; Kao, J. P.; Roubinian, N. H.; Page, G. P.; Eisenmesser, E. Z.; Luzzatto, L.; Zimring, J. C.; Buehler, P. W.; Janetzko, J.; D'Alessandro, A.
Show abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy, yet how donor alleles shape red blood cell (RBC) storage, transfusion performance, and recipient physiology remains unresolved. Across 13,091 donors, a recalled cohort, donor-recipient data, humanized mice, and a prospective sickle cell disease cohort, variants reduced G6PD abundance, constrained pentose phosphate pathway flux and redox metabolism, and accelerated age-dependent functional decay. Murine A-; RBCs recovered poorly; A-; and Mediterranean RBCs impaired renal oxygenation, especially the latter, which caused greater plasma hemolysis. In humans, A-; units yielded smaller hemoglobin increments, while deficient units reduced allogeneic 51Cr post-transfusion recovery and four-week survival by 8 and 12-percentage-points. NADP;-bound cryo-EM resolved mechanisms: remodeling of the catalytic NADP;-binding region and dimer interface underlies A-; kinetic fragility, whereas Mediterranean S188F exhibits temperature-dependent oligomerization and conformational instability. These findings define an allelic series linking genotype to molecular instability, RBC quality, transfusion performance, and recipient physiology.
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