Novel mechanisms of PIEZO1 dysfunction in hereditary xerocytosis

Edyta Glogowska, Eve R. Schneider, Yelena Maksimova, Vincent P. Schulz, Kimberly Lezon-Geyda, John Wu, Kottayam Radhakrishnan, Siobán B. Keel, Donald Mahoney, Alison M. Freidmann, Rachel A. Altura, Elena O. Gracheva, Sviatoslav N. Bagriantsev, Theodosia A. Kalfa, Patrick G. Gallagher

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Mutations in PIEZO1 are the primary cause of hereditary xerocytosis, a clinically heterogeneous, dominantly inherited disorder of erythrocyte dehydration. We used nextgeneration sequencing-based techniques to identify PIEZO1 mutations in individuals from 9 kindreds referred with suspected hereditary xerocytosis (HX) and/or undiagnosed congenital hemolytic anemia. Mutations were primarily found in the highly conserved, COOH-terminal pore-region domain. Several mutations were novel and demonstrated ethnic specificity. We characterized these mutations using genomic-, bioinformatic-, cell biology-, and physiology-based functional assays. For these studies, we created a novel, cell-based in vivo system for study of wild-type and variant PIEZO1 membrane protein expression, trafficking, and electrophysiology in a rigorous manner. Previous reports have indicated HX-associated PIEZO1 variants exhibit a partial gain-of-function phenotype with generation of mechanically activated currents that inactivate more slowly than wild type, indicating that increased cation permeability may lead to dehydration of PIEZO1-mutant HX erythrocytes. In addition to delayed channel inactivation, we found additional alterations in mutant PIEZO1 channel kinetics, differences in response to osmotic stress, and altered membrane protein trafficking, predicting variant alleles that worsen or ameliorate erythrocyte hydration. These results extend the genetic heterogeneity observed in HX and indicate that various pathophysiologic mechanisms contribute to the HX phenotype.

Original languageEnglish
Pages (from-to)1845-1856
Number of pages12
Issue number16
StatePublished - Oct 19 2017

Bibliographical note

Publisher Copyright:
© 2017 by The American Society of Hematology.

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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