Abstract
Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2α and Tfr2β). Tfr2α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days' and 10 weeks' old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β (Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2α in modulation of erythropoiesis and of Tfr2β in favoring iron availability for erythropoiesis.
Highlights
Type 3 haemochromatosis (HFE3) is an autosomal recessive genetic disorder that leads to an accumulation of iron both in the blood and in several tissues, especially in the liver
Our results indicate that the lack of Tfr2α influences bone marrow (BM) and splenic erythropoiesis starting from an early stage of life
The pattern of erythropoiesis was observed to be different in WT and Tfr2 mice across the lifespan
Summary
Type 3 haemochromatosis (HFE3) is an autosomal recessive genetic disorder that leads to an accumulation of iron both in the blood and in several tissues, especially in the liver. HFE3 patients have elevated transferrin saturation (TS) and serum ferritin level (sFt) [1]. This disease is caused by mutations in transferrin receptor 2 (TFR2) gene [2] that codes for two main isoforms, namely, Tfr alpha (Tfr2α) and Tfr beta (Tfr2β), that show moderate homology to the type 1 transferrin receptor (Tfr1) [3]. The levels of this protein in plasma membrane are regulated by TS, with an increased stabilization in the presence of highly saturated transferrin [6, 7]. The transcription of the entire TFR2 gene gives rise to the Tfr2α isoform which is a transmembrane protein. Some mutations affect only the Tfr2α isoform, while others, such as M172K, abolish the Tfr2β methionine starting codon [9, 10]
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