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 (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.