Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection

Shang Ma, Stuart Cahalan, Gregory LaMonte, Nathan D. Grubaugh, Weizheng Zeng, Swetha E. Murthy, Emma Paytas, Ramya Gamini, Viktor Lukacs, Tess Whitwam, Meaghan Loud, Rakhee Lohia, Laurence Berry, Shahid M. Khan, Chris J. Janse, Michael Bandell, Christian Schmedt, Kai Wengelnik, Andrew I. Su, Eric HonoreElizabeth A. Winzeler, Kristian G. Andersen, Ardem Patapoutian

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)443-455.e12
JournalCell
Volume173
Issue number2
DOIs
StatePublished - Apr 5 2018
Externally publishedYes

Keywords

  • PIEZO1
  • cerebral malaria
  • dehydration
  • functional variants
  • genomics
  • human genetics
  • ion channel
  • malaria
  • mechanotransduction
  • red blood cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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