{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:58:31Z","timestamp":1784170711920,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,10]],"date-time":"2025-08-10T00:00:00Z","timestamp":1754784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health\u2014Current research IRCCS, Fondazione IRCCS Ca\u2019 Granda Policlinico Milano","award":["RC2024 175\/01"],"award-info":[{"award-number":["RC2024 175\/01"]}]},{"name":"Italian Ministry of Health\u2014Current research IRCCS, Fondazione IRCCS Ca\u2019 Granda Policlinico Milano","award":["101120168"],"award-info":[{"award-number":["101120168"]}]},{"name":"European Union\u2019s MASCA Horizon 2020 acronym INNOVATION","award":["RC2024 175\/01"],"award-info":[{"award-number":["RC2024 175\/01"]}]},{"name":"European Union\u2019s MASCA Horizon 2020 acronym INNOVATION","award":["101120168"],"award-info":[{"award-number":["101120168"]}]},{"name":"European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet)","award":["RC2024 175\/01"],"award-info":[{"award-number":["RC2024 175\/01"]}]},{"name":"European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet)","award":["101120168"],"award-info":[{"award-number":["101120168"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (ATP11C), located on the X chromosome, encodes the major phosphatidylserine flippase in human erythroid cells. Only five patients have so far been reported with defective ATP11C, displaying mild hemolytic anemia and reduced flippase activity. In this study, we report four Italian male patients in three unrelated families with novel private mutations in the ATP11C gene, resulting in impaired flippase activity associated with mild\/compensated hemolytic anemia. The decreased flippase activity was measured as % of phosphatidylserine internalization over time and ranged after 20 min incubation from 5% to 18.6% in all patients, regardless of the type of molecular defect. Flippase activity was also tested in healthy controls, ranging from 43% to 62% in both males and females. This measurement appears to be a useful tool for hypothesizing ATP11C abnormalities in male subjects with mild compensated hemolysis, prior to next generation sequencing (NGS) analysis. Although rare, ATP11C mutations may be underrecognized, and therefore should be suspected and investigated in male patients presenting with subtle hemolytic signs or symptoms.<\/jats:p>","DOI":"10.3390\/ijms26167722","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:02:09Z","timestamp":1754910129000},"page":"7722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Not-So-Rare Defects of RBC Lipidic Composition: Four New Cases of Flippase Deficiency Due to ATP11C Mutations"],"prefix":"10.3390","volume":"26","author":[{"given":"Elisa","family":"Fermo","sequence":"first","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1933-6415","authenticated-orcid":false,"given":"Elena","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Flow Cytometry Service, Clinical Pathology, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Paola","family":"Marcello","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7742-1979","authenticated-orcid":false,"given":"Cristina","family":"Vercellati","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia Maria","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8614-3904","authenticated-orcid":false,"given":"Anna","family":"Zaninoni","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1521-3319","authenticated-orcid":false,"given":"Valentina","family":"Brancaleoni","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-1349","authenticated-orcid":false,"given":"Elena","family":"Di Pierro","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Beneventi","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0579-0934","authenticated-orcid":false,"given":"Marta","family":"Tornese","sequence":"additional","affiliation":[{"name":"Flow Cytometry Service, Clinical Pathology, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Fattizzo","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-5355","authenticated-orcid":false,"given":"Tommaso","family":"Casini","sequence":"additional","affiliation":[{"name":"Department of Haematology-Oncology, Meyer University Children\u2019s Hospital, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Corti","sequence":"additional","affiliation":[{"name":"Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5976-5233","authenticated-orcid":false,"given":"Paola","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Hematology, Physiopathology of Anemia Unit, Fondazione IRCCS Ca\u2019Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.hoc.2019.01.002","article-title":"Rare Hereditary Hemolytic Anemias: Diagnostic Approach and Considerations in Management","volume":"33","author":"Risinger","year":"2019","journal-title":"Hematol. 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