Common Piezo1 allele in African populations causes xerocytosis and attenuates Plasmodium infection

Ma, S.; Cahalan, S.; Lohia, R.; LaMonte, G.; Zeng, W.; Murthy, S.; Paytas, E.; Grubaugh, N. D.; Gamini, R.; Berry, L.; Lukacs, V.; Whitwam, T.; Loud, M.; Su, A. I.; Andersen, K. G.; Winzeler, E. A.; Honore, E.; Wengelnik, K.; Patapoutian, A.

doi:10.1101/159830

bioRxiv · 10.1101/159830

Common Piezo1 allele in African populations causes xerocytosis and attenuates Plasmodium infection

Ma, S.·Cahalan, S.·Lohia, R.·LaMonte, G.·Zeng, W.·Murthy, S.·Paytas, E.·Grubaugh, N. D.·Gamini, R.·Berry, L.·Lukacs, V.·Whitwam, T.·Loud, M.·Su, A. I.·Andersen, K. G.·Winzeler, E. A.·Honore, E.·Wengelnik, K.·Patapoutian, A.

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Abstract

Hereditary xerocytosis (HX) is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. Gain-of-function (GOF) mutations in mechanosensitive Piezo1 ion channels are identified in HX patients. RBC dehydration is linked to reduced Plasmodium infection rates in vitro. We engineered a Piezo1 mouse model of HX and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice. Furthermore, we identified a novel GOF human Piezo1 variant, E756del, present in a third of African population. Remarkably, RBCs from individuals carrying this allele are dehydrated and protected against Plasmodium infection in vitro. The presence of an HX-causing Piezo1 mutation at such high frequencies in African population is surprising, and suggests an association with malaria resistance.

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Ma, S., Cahalan, S., Lohia, R., LaMonte, G., Zeng, W., Murthy, S., Paytas, E., Grubaugh, N. D., Gamini, R., Berry, L., Lukacs, V., Whitwam, T., Loud, M., Su, A. I., Andersen, K. G., Winzeler, E. A., Honore, E., Wengelnik, K., Patapoutian, A.. 2017-07-06. Common Piezo1 allele in African populations causes xerocytosis and attenuates Plasmodium infection. https://doi.org/10.1101/159830

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