Increased levels of ERFE-encoding FAM132B in patients with congenital dyserythropoietic anemia type II

Recessive mutations in SEC23B gene cause congenital dyserythropoietic anemia type II (CDAII),1 a rare hereditary disorder hallmarked by ineffective erythropoiesis, iron overload, and reduced expression of hepatic hormone hepcidin.2,3 Some erythroid regulators have been proposed as pathological suppressors of hepcidin expression, such as growth differentiation factor 15 (GDF15) in thalassemia, CDAI and II,4-6 even if alone it seems not necessary for physiological hepcidin suppression.7 The most recently described is the erythroblast-derived hormone erythroferrone (ERFE), a member of TNF-α superfamily that specifically inhibits hepcidin production. ERFE-encoding FAM132B is an erythropoietin (EPO)-responsive gene in experimental models.8 However, the function of ERFE in humans remains to be investigated. This study provides the first analysis on ERFE expression in human model of dyserythropoietic anemia with ineffective erythropoiesis, such as CDAII. Our ex vivo and in vitro data indicate that ERFE over-expression in CDAII patients might be most likely related to both physiological and pathological mechanisms leading to hepcidin suppression in condition of dyserythropoiesis. Indeed, we clearly demonstrated that in two different genetic conditions sharing common clinical findings and similar pathogenesis, such as CDAII and BT-intermedia, FAM132B over-expression is related to the abnormal erythropoiesis. Nevertheless, the absence of a clear correlation between erythroferrone levels and CDAII iron balance suggest that ERFE cannot be the only erythroid regulator of hepcidin suppression, at least in CDAII patients.