The correlation of the RBC MCV with serum transferrin saturation in patients with gain-of-function or loss-of-function FPN mutations. (A) MCV vs transferrin (Tf) saturation plot of FPN loss-of-function (blue) and gain-of-function (red) mutations. (B) Linear regression of MCV vs Tf saturation showed that the MCVs of gain-of-function mutations increased as serum Tf saturations increased, whereas MCVs of loss-of-function mutations did not. The MCV and Tf saturation data of patients were obtained from literature, and the mutations were classified as gain-of-function mutations or loss-of-function mutations based on reports also.^10,36,38-40  Consistent with our hypothesis, these results suggest that erythroblasts with loss-of-function FPN mutations use retained intracellular iron to synthesize hemoglobin and were relatively insensitive to serum iron perturbations, leading to higher MCV values relative to low Tf saturations. By contrast, erythroblasts with gain-of-function mutations readily export iron out of cells and are sensitive to serum iron fluctuations.