Ma, Shang, Cahalan, Stuart, Rakhee, Lohia, Gregory, LaMonte, Weizheng, Zeng, Swetha, Murthy, Emma, Paytas, Nathan D, Grubaugh, Ramya, Gamini, Laurence, Berry, Viktor, Lukacs, Tess, Whitwam, Meaghan, Loud, Schmedt, Christian, Andrew I, Su, Kristian G, Andersen, Elizabeth A, Winzeler, Eric, Honore, Kai, Wengelnik and Ardem, Patapoutian (2018) Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection. Cell, 173 (2). 443-455.e12. ISSN 10974172

Abstract

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance. A gain-of-function mutation in the mechanically activated channel PIEZO1 is associated with resistance to the malaria parasite Plasmodium falciparum.

Item Type:	Article
Keywords:	cerebral malaria dehydration functional variants genomics human genetics ion channel malaria mechanotransduction PIEZO1 red blood cell
Date Deposited:	04 May 2018 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/33704