The anemia of "haemoglobin-deficit" (hbd/hbd) mice is caused by a defect in transferrin cycling
Abstract
The hemoglobin-deficit mouse mutant (hbd) is characterized by a hypochromic, microcytic anemia that is inherited in an autosomal, recessive manner. The recently identified gene responsible, Sec15l1, is specific to hematopoietic stem cells and is homologous to a gene encoding a member of the exocyst pathway in yeast. However, the defective cellular mechanism underlying the hemoglobin deficiency in hbd/hbd mice has not been functionally identified. Here we investigated the possibility that erroneous transferrin trafficking is responsible for the hbd phenotype. Reticulocytes were harvested from hbd/hbd mice and from background- and age-matched controls. Iron and transferrin uptake and iron utilization experiments were performed using 59Fe- or 125I-transferrin to follow the trafficking and utilization of the protein and metal. Compared to controls, iron and transferrin uptake as well as iron incorporation into heme was compromised in hbd reticulocytes. Importantly, reduced heme synthesis in these cells was restored to normal values by using an iron source that bypasses the transferrin-receptor pathway. We also found that +/+ and hbd reticulocytes take up free, ferrous iron at identical rates, while the rates of Tf internalization a...Continue Reading
References
Citations
Substantial changes of cellular iron homeostasis during megakaryocytic differentiation of K562 cells
Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis.
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