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

Cell. 2018 Apr 5;173(2):443-455.e12. doi: 10.1016/j.cell.2018.02.047. Epub 2018 Mar 22.

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.

Keywords: PIEZO1; cerebral malaria; dehydration; functional variants; genomics; human genetics; ion channel; malaria; mechanotransduction; red blood cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Alleles
  • Anemia, Hemolytic, Congenital / genetics
  • Anemia, Hemolytic, Congenital / pathology*
  • Animals
  • Dehydration
  • Disease Models, Animal
  • Erythrocytes / cytology
  • Erythrocytes / metabolism
  • Gene Deletion
  • Genotype
  • Humans
  • Hydrops Fetalis / genetics
  • Hydrops Fetalis / pathology*
  • Intermediate-Conductance Calcium-Activated Potassium Channels / deficiency
  • Intermediate-Conductance Calcium-Activated Potassium Channels / genetics
  • Ion Channels / chemistry
  • Ion Channels / genetics*
  • Malaria / genetics
  • Malaria / parasitology
  • Malaria / pathology*
  • Malaria / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Plasmodium berghei / growth & development
  • Plasmodium berghei / pathogenicity
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism

Substances

  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Ion Channels
  • Kcnn4 protein, mouse
  • PIEZO1 protein, human
  • Piezo1 protein, mouse

Supplementary concepts

  • Xerocytosis, hereditary