Rbm38 Deficiency Impairs Erythroid Heme Biosynthesis and Induces Porphyria via Reduced Ferrochelatase Expression Available to Purchase

• Rbm38 is essential for bone marrow RBC production and erythroid heme biosynthesis.

• Rbm38 deficiency disrupts the splicing, stability, and translation of Fech, resulting in an EPP-like disorder in mice.

RNA splicing and processing are critical for erythropoiesis, as dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. While in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- red blood cells exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, mRNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.