PIEZO1 gain-of-function mutations delay reticulocyte maturation in hereditary xerocytosis

Moura, Pedro L.; Hawley, Bethan R.; Dobbe, Johannes G.G.; Streekstra, Geert J.; Rab, Minke A.E.; Bianchi, Paola; Van Wijk, Richard; Toye, Ashley M.; Satchwell, Timothy J.

Abstract

Dehydrated hereditary stomatocytosis 1 or hereditary xerocytosis (HX, OMIM 194380) is a rare hereditary autosomal dominant disorder characterized by hemolytic anemia and red blood cell (RBC) dehydration. The occurrence of HX is linked with gain-of-function mutations in PIEZO1, the gene encoding for the mechanosensitive non-specific cation channel PIEZO121 which is activated by shear-stress and in concert with other ion channels (particularly the Gardos potassium calcium-activated channel, KCNN4) regulates cell volume homeostasis and metabolic activity in the RBC.3 Intriguingly, PIEZO1 gain-of-function mutations have recently been reported to occur at a much higher frequency within the population than had been previously described and have also been implicated in malaria resistance,4 suggesting that the mechanisms underpinning HX may merit further investigation. Since reticulocytosis is one of the hallmarks of HX,5 we sought to determine whether altered reticulocyte maturation could be a causative agent of this phenotype. We characterize reticulocytes and erythrocytes from 10 HX patients in comparison to healthy controls, revealing alterations in deformability and vesicle content that implicate a maturational defect in HX. We further demonstrate that HX patients suffer from impaired reticulocyte maturation as assayed through differences in the extent and rate of loss of CD71 and RNA content over time and that this effect can be recapitulated in healthy reticulocytes upon chemically-induced PIEZO1 overactivation, providing a functional link to the reticulocytosis phenotype present in HX.

• Journal Article Type: Letter
• Online Publication Date: Jun 1, 2020
• Publication Date: Jun 1, 2020
• Deposit Date: Jul 11, 2024
• Publicly Available Date: Jul 12, 2024
• Journal: Haematologica
• Print ISSN: 0390-6078
• Electronic ISSN: 1592-8721
• Publisher: Ferrata Storti Foundation
• Peer Reviewed: Peer Reviewed
• Volume: 105
• Issue: 6
• Pages: E268-E271
• DOI: https://doi.org/10.3324/haematol.2019.231159
• Public URL: https://uwe-repository.worktribe.com/output/12120192