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A novel missense variant in $ATP11C$ is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia

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  • معلومة اضافية
    • Publisher Information:
      Wiley-Blackwell Publishing, Inc. 2023-12-01
    • نبذة مختصرة :
      Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (ATP11C) encodes the major phosphatidylserine (PS) flippase in human red blood cells (RBCs). Flippases actively transport phospholipids (e.g., PS) from the outer to the inner leaflet to establish and maintain phospholipid asymmetry of the lipid bilayer of cell membranes. This asymmetry is crucial for survival since externalized PS triggers phagocytosis by splenic macrophages. Here we report on pathophysiological consequences of decreased flippase activity, prompted by a patient with hemolytic anemia and hemizygosity for a novel c.2365C > T p.(Leu789Phe) missense variant in ATP11C. ATP11C protein expression was strongly reduced by 58% in patient‐derived RBC ghosts. Furthermore, functional characterization showed only 26% PS flippase activity. These results were confirmed by recombinant mutant ATP11C protein expression in HEK293T cells, which was decreased to 27% compared to wild type, whereas PS‐stimulated ATPase activity was decreased by 57%. Patient RBCs showed a mild increase in PS surface exposure when compared to control RBCs, which further increased in the most dense RBCs after RBC storage stress. The increase in PS was not due to higher global membrane content of PS or other phospholipids. In contrast, membrane lipid lateral distribution showed increased abundance of cholesterol‐enriched domains in RBC low curvature areas. Finally, more dense RBCs and subtle changes in RBC morphology under flow hint toward alterations in flow behavior of ATP11C‐deficient RBCs. Altogether, ATP11C deficiency is the likely cause of hemolytic anemia in our patient, thereby underlining the physiological role and relevance of this flippase in human RBCs.
    • الموضوع:
      Institute of Veterinary Physiology; 570 Life sciences; biology; Hematology; Journal Article; PeerReviewed; info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion
    • Availability:
      Open access content. Open access content
      info:eu-repo/semantics/openAccess
      Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
      http://creativecommons.org/licenses/by-nc-nd/4.0
      info:eu-repo/semantics/openAccess
    • Note:
      application/pdf
      info:doi/10.5167/uzh-237166
      English
      English
    • Other Numbers:
      CHUZH oai:www.zora.uzh.ch:237166
      https://www.zora.uzh.ch/id/eprint/237166/8/van_Dijk_American_J_Hematol_2023.pdf
      info:doi/10.5167/uzh-237166
      info:doi/10.1002/ajh.27088
      info:pmid/37671681
      urn:issn:0361-8609
      1443053433
    • Contributing Source:
      HAUPTBIBLIOTHEK UNIV OF ZURICH
      From OAIster®, provided by the OCLC Cooperative.
    • الرقم المعرف:
      edsoai.on1443053433
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