{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:58:32Z","timestamp":1784170712878,"version":"3.55.0"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene <jats:italic>(ATP11C)<\/jats:italic> 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\u2009&gt;\u2009T p.(Leu789Phe) missense variant in <jats:italic>ATP11C<\/jats:italic>. ATP11C protein expression was strongly reduced by 58% in patient\u2010derived 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\u2010stimulated 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\u2010enriched 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\u2010deficient 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.<\/jats:p>","DOI":"10.1002\/ajh.27088","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:29:23Z","timestamp":1693996163000},"page":"1877-1887","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A novel missense variant in <scp><i>ATP11C<\/i><\/scp> is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9377-0367","authenticated-orcid":false,"given":"Myrthe J.","family":"van Dijk","sequence":"first","affiliation":[{"name":"Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht The Netherlands"},{"name":"Center for Benign Hematology, Thrombosis and Hemostasis\u2014Van Creveldkliniek University Medical Center Utrecht, Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte A.","family":"van Oirschot","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-4725","authenticated-orcid":false,"given":"Alexander N.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1235-1521","authenticated-orcid":false,"given":"Steffen M.","family":"Recktenwald","sequence":"additional","affiliation":[{"name":"Department of Experimental Physics Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-6824","authenticated-orcid":false,"given":"Min","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Experimental Physics Saarland University  Saarbr\u00fccken Germany"},{"name":"Theoretical Medicine and Biosciences Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4761-8521","authenticated-orcid":false,"given":"Amaury","family":"Stommen","sequence":"additional","affiliation":[{"name":"CELL Unit and PICT Platform, de Duve Institute UCLouvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Sophie","family":"Cloos","sequence":"additional","affiliation":[{"name":"CELL Unit and PICT Platform, de Duve Institute UCLouvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Vanderroost","sequence":"additional","affiliation":[{"name":"CELL Unit and PICT Platform, de Duve Institute UCLouvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romano","family":"Terrasi","sequence":"additional","affiliation":[{"name":"Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute UCLouvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6590-2804","authenticated-orcid":false,"given":"Kuntal","family":"Dey","sequence":"additional","affiliation":[{"name":"Red Blood Cell Group, Institute of Veterinary Physiology University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Bos","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory\u2014Research, University Medical Center Utrecht Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minke A. 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