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

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• The ATP11C gene encodes the primary phosphatidylserine flippase in human red blood cells.
• Defects in ATP11C are rare, with only five patients previously reported, exhibiting mild hemolytic anemia and reduced flippase activity.

Purpose of the Study:

• To identify and characterize novel mutations in the ATP11C gene in Italian male patients with unexplained hemolytic anemia.
• To evaluate the diagnostic utility of measuring phosphatidylserine flippase activity in patients with suspected ATP11C deficiency.

Main Methods:

• Genetic analysis of the ATP11C gene in four male patients from three families.
• Measurement of phosphatidylserine flippase activity via phosphatidylserine internalization assay.
• Comparison of patient flippase activity with that of healthy controls.

Main Results:

• Four novel private mutations in the ATP11C gene were identified in the patients.
• All patients exhibited significantly impaired flippase activity (5-18.6% after 20 min) compared to healthy controls (43-62%).
• The observed flippase defect correlated with mild or compensated hemolytic anemia.

Conclusions:

• Novel ATP11C mutations can cause mild hemolytic anemia in males.
• Phosphatidylserine flippase activity assay is a valuable preliminary tool for diagnosing ATP11C abnormalities in males with subtle hemolytic signs.
• ATP11C mutations may be underdiagnosed and warrant investigation in relevant patient populations.