Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels

Juliette Albuisson, Swetha E. Murthy, Michael Bandell, Bertrand Coste, Hélène Louis-Dit-Picard, Jayanti Mathur, Madeleine Fénéant-Thibault, Gérard Tertian, Jean Pierre De Jaureguiberry, Pierre Yves Syfuss, Stuart Cahalan, Loic Garçon, Fabienne Toutain, Pierre Simon Rohrlich, Jean Delaunay, Véronique Picard, Xavier Jeunemaitre, Ardem Patapoutian

Research output: Contribution to journalArticlepeer-review

222 Scopus citations


Dehydrated hereditary stomatocytosis is a genetic condition with defective red blood cell membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations in the mechanically activated PIEZO1 (FAM38A) ion channel were associated with dehydrated hereditary stomatocytosis. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated dehydrated hereditary stomatocytosis cases, we identify three novel missense mutations and one recurrent duplication in PIEZO1, demonstrating that it is the major gene for dehydrated hereditary stomatocytosis. All the dehydrated hereditary stomatocytosis-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in red blood cells of dehydrated hereditary stomatocytosis patients. Our findings also suggest a new role for mechanotransduction in red blood cell biology and pathophysioloy.

Original languageEnglish (US)
Article number1884
JournalNature communications
StatePublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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