MbShea@PWP@English@UMCP

HRG1 (Heme Responsive Gene) was the first eukaryotic heme transporter/importer to be identified. Knockdown of HRG1 in zebrafish causes anemia, embryonic lethality, or severe developmental phenotypes. In mammals, HRG1 is involved in recycling heme from effete red blood cells in the phagolysosomal compartment of reticuloendothelial macrophages. We asked the question: are there naturally occurring variants in the human HRG1 (hHRG1) gene which would negatively affect heme transport function. Because Saccharomyces cerevisiae lacks the ability to utilize exogenous heme, knockout of endogenous heme synthesis (hem1Δ) causes lethality, unless these cells express HRG1 in the presence of heme. We exploited the hem1Δ strain to analyze variants in hHRG1. A search of human genome databases identified 55 missense variants all of which were expressed in hem1Δ yeast and growth monitored. Three of the variants resulted in severe reduction in growth phenotype, while six resulted in a moderate growth phenotype indicating potential loss-of-function or severe hypomorphic alleles. The variants were expressed in HEK293 cells to test their localization in mammalian cells. Given the striking phenotypes associated with HRG1 depletion in zebrafish, we speculate that missense variants in hHRG1 may pre-dispose specific individuals to hematological disorders including anemia. Further characterization of these variants may lead to novel therapeutic strategies to ameliorate iron deficiency anemia, the most common nutrition disorder in the world.
WC: 217
Reader's response: A reader may find the topic dull and could struggle to see the relevance of heme transport studies conducted in C. elegans. I will try to hook the reader in the introduction using statistics about iron-deficiency anemia and explaining the functional conservation of HRG1

W, good plan. I like the use of "We" here. I am a big advocate of using this voice in science because this is truthful. We work together. We generate hypotheses, we make inferences....