Not-So-Rare Defects of RBC Lipidic Composition: Four New Cases of Flippase Deficiency Due to ATP11C Mutations

Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (<i>ATP11C</i>), located on the X chromosome, encodes the major phosphatidylserine flippase in human erythroid cells. Only five patients have so far been reported with defective <i>ATP11C</i>, 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 <i>ATP11C</i> 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 <i>ATP11C</i> abnormalities in male subjects with mild compensated hemolysis, prior to next generation sequencing (NGS) analysis. Although rare, <i>ATP11C</i> mutations may be underrecognized, and therefore should be suspected and investigated in male patients presenting with subtle hemolytic signs or symptoms.