@article{9819b94bbb1648d7abaf397fe46d836c,
title = "Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection",
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.",
keywords = "PIEZO1, cerebral malaria, dehydration, functional variants, genomics, human genetics, ion channel, malaria, mechanotransduction, red blood cell",
author = "Shang Ma and Stuart Cahalan and Gregory LaMonte and Grubaugh, {Nathan D.} and Weizheng Zeng and Murthy, {Swetha E.} and Emma Paytas and Ramya Gamini and Viktor Lukacs and Tess Whitwam and Meaghan Loud and Rakhee Lohia and Laurence Berry and Khan, {Shahid M.} and Janse, {Chris J.} and Michael Bandell and Christian Schmedt and Kai Wengelnik and Su, {Andrew I.} and Eric Honore and Winzeler, {Elizabeth A.} and Andersen, {Kristian G.} and Ardem Patapoutian",
note = "Funding Information: We thank Ali Torkamani for advice on genomics, Dominic Kwiatkowski and Ilya Shlyakhter for discussions, and Lisa Stowers for reading the manuscript. This work was partly supported by NIH grants R01 DE022358 to A.P. and AI090141 and AI103058 to E.A.W. S.M. is supported by a Calibr-GHDDI Gates postdoctoral fellowship . G.L. is supported by an A.P. Giannini postdoctoral fellowship . K.G.A. is a Pew Biomedical Scholar and is supported by NIH NCATS CTSA UL1TR001114 . A.P. is an investigator of the Howard Hughes Medical Institute . Funding Information: We thank Ali Torkamani for advice on genomics, Dominic Kwiatkowski and Ilya Shlyakhter for discussions, and Lisa Stowers for reading the manuscript. This work was partly supported by NIH grants R01 DE022358 to A.P. and AI090141 and AI103058 to E.A.W. S.M. is supported by a Calibr-GHDDI Gates postdoctoral fellowship. G.L. is supported by an A.P. Giannini postdoctoral fellowship. K.G.A. is a Pew Biomedical Scholar and is supported by NIH NCATS CTSA UL1TR001114. A.P. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = apr,
day = "5",
doi = "10.1016/j.cell.2018.02.047",
language = "English (US)",
volume = "173",
pages = "443--455.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}