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Cited by 250Erythrocyte Function and PathophysiologyMalaria Research and ControlHemoglobinopathies and Related Disorders

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

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Ma, Shang, Cahalan, Stuart, LaMonte, Gregory, Grubaugh, Nathan D., Zeng, Weizheng, Murthy, Swetha E., Paytas, Emma, Gamini, Ramya +15 more·2018·Cell
DOI 10.1016/j.cell.2018.02.047PMC PMC5889333

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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.

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  • In a cohort of African American patients over the age of 40 years carrying the E756del Piezo1 polymorphism, comparable elevations in serum ferritin, transferrin saturation, and hepcidin levels were observed.

    “Similarly, in a cohort of African American patients over the age of 40 years carrying the E756del Piezo1 polymorphism, comparable elevations in serum ferritin, transferrin saturation, and hepcidin levels were observed.”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [125]

    The Results section on African American E756del carriers reports nine carriers among 25 healthy blood donors and describes RBC dehydration, but does not establish that the donors were over 40. Neither that section nor the searched passages report elevations in serum ferritin, transferrin saturation, or hepcidin (searched: those markers and age 40). (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Macrophages expressing E756del Piezo1 exhibit increased erythrocyte turnover, resulting in elevated erythroferrone levels in adult mice and reduced hepcidin expression.

    “Macrophages expressing E756del Piezo1 exhibited increased erythrocyte turnover, resulting in elevated erythroferrone levels in adult mice and reduced hepcidin expression.125”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [125]

    The Results section on macrophage-specific gain-of-function Piezo1 reports malaria survival and parasitemia, not erythrocyte turnover. Searches for erythroferrone, hepcidin, and E756del macrophages found no passage in our copy addressing the claimed chain of effects in adult mice. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

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References 75 · Cited by 250

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Authors
Ma, S., Cahalan, S., LaMonte, G., Grubaugh, N. D., Zeng, W., Murthy, S. E., Paytas, E., Gamini, R., Lukacs, V., Whitwam, T., Loud, M., Lohia, R., Berry, L., Khan, S. M., Janse, C. J., Bandell, M., Schmedt, C., Wengelnik, K., Su, A. I., Honore, E., Winzeler, E. A., Andersen, K. G., & Patapoutian, A.
Affiliations
  • Scripps Research Institute (US)
  • University of California San Diego (US)
  • Centre National de la Recherche Scientifique (FR)
  • Leiden University Medical Center (NL)
  • Genomics Institute of the Novartis Research Foundation (US)
Corresponding author
Patapoutian, Ardem
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-04
Volume
173
Issue
2
Pages
443-455.e12
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.02.047
PMC
PMC5889333
OpenAlex
W2792625647
Cited by
250
References
75
Citations by year
2026: 16 · 2025: 31 · 2024: 40 · 2023: 30 · 2022: 31 · 2021: 42 · 2020: 25 · 2019: 25 · 2018: 9 · 2017: 1
FWCI
17.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion)
  • HAL (submittedVersion)
  • The Novartis Repository (Novartis) (submittedVersion)
Funders
  • NIH (R01 DE022358, AI090141, AI103058)
  • Calibr-GHDDI Gates postdoctoral fellowship
  • A.P. Giannini postdoctoral fellowship
  • Pew Biomedical Scholar
  • NIH NCATS CTSA (UL1TR001114)
  • Howard Hughes Medical Institute
Topics
  • Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
Piezo1, hereditary xerocytosis, red blood cell dehydration, malaria, malaria resistance, gain-of-function mutations, experimental cerebral malaria, T cells, mechanosensitive ion channels, African populations, mouse model
MeSH terms
Alleles, Anemia, Hemolytic, Congenital, Animals, Dehydration, Disease Models, Animal, Erythrocytes, Genotype, Humans, Ion Channels, Malaria, Mice, Inbred C57BL, Phenotype, Plasmodium berghei, T-Lymphocytes, Hydrops Fetalis, Gene Deletion, Mice, Knockout, Black People, Mice, Intermediate-Conductance Calcium-Activated Potassium Channels

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