Lipid Metabolism Transcriptomic Signature of Defective Erythropoiesis in Diamond Blackfan Anemia syndrome.

Analysis of Diamond Blackfan anemia syndrome (DBAS) cohorts and animal models have not revealed a potential mechanism for the variable anemia phenotype, a key feature of this disease. Here, we utilized an established Rpl5Skax23-Jus/+ murine DBAS model in order to study this dynamic erythropoiesis deficiency. These haploinsufficient mice exhibit variably penetrant craniofacial and cardiac defects mimicking the phenotypes of DBAS patients bearing RPL5 mutations. We additionally discovered that this specific heterozygous splicing mutation is pathogenic and leads to partial intron retention. By examining the transcriptome of fetal liver erythroid progenitors at E12.5, we demonstrate downregulation of erythroid differentiation pathways consistent with the DBAS phenotype. We also identified dysregulated transcription of lipid metabolism genes with significant reduction in Scd1 expression in the subset of E12.5 mutant embryos at risk for erythroid failure. SCD1, a key enzyme that converts saturated to monounsaturated fatty acids, has not been previously linked to erythropoiesis or DBAS. When anemia was induced in adult Rpl5Skax23-Jus/+ mice, mutant mice exhibited delayed erythroid recovery, whereas pretreatment with an SCD1 inhibitor resulted in improved erythropoiesis in both wildtype and mutant mice. This analysis suggests a potential role of lipid metabolism in the variable anemia penetrance in DBAS and highlights a previously unappreciated pathway that requires further study as a potential target for drug development.