biostudies-literatureMa SNCATS NIH HHSNIDCR NIH HHSNIH NCATS CTSAHoward Hughes Medical InstituteNIAID NIH HHSCalibr-GHDDI Gates postdoctoral fellowshipPew Biomedical ScholarA.P. Giannini postdoctoral fellowshipNIH443-455.e12https://www.ebi.ac.uk/biostudies/studies/S-EPMC5889333biostudies-literatureUnknown173(2)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 deCellCommon PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection.PMC5889333UL1TR001114UL1 TR001114R01 AI090141R01 AI103058R01 DE022358T32 AI007244AI103058AI090141Lohia RSu AIMa SKhan SMPaytas EGamini RSchmedt CLukacs VWhitwam TZeng WHonore EPatapoutian ABerry LGrubaugh NDAndersen KGJanse CJBandell MWinzeler EALoud MCahalan SLaMonte GWengelnik KMurthy SEfalseCommon PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection.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 de2018-01-01T00:00:00Z2018 Apr2026-05-03T07:54:27.55Z2019-06-06T19:17:55ZS-EPMC58893332957645010.1016/j.cell.2018.02.047