Altered translation efficiency of specific mRNAs in a zebrafish model of Diamond-Blackfan anemia syndrome

Diamond-Blackfan anemia syndrome (DBAS) is a congenital pure red-cell aplasia that is often accompanied by physical deformities. Heterozygous mutations in more than 20 ribosomal protein (RP) genes have been linked to the disease. The most frequently mutated gene is RPS19, which accounts for 25% of the patients. Haploinsufficiency of the RP genes may affect translation of specific mRNAs that could be related to the anemia. However, the underlying mechanisms are still unclear. To evaluate the impacts of RP depletion on translation, using a zebrafish model of DBAS with knockdown of the RPS19 ortholog (rps19), we compared changes in polysomal mRNAs with those in total mRNAs in the DBAS model to examine the translation efficiency of individual transcripts. As a result, we calculated the translation efficiency of 5464 transcripts. Among them, the transcripts from 75 genes exhibited translational repression to less than half compared to the controls. Erythropoiesis-related genes were enriched among the repressed genes. Unexpectedly, some genes related to glycan biosynthesis were also translationally repressed. One of these was the pigq gene, which participates in a glycosylphosphatidylinositol-anchor biosynthesis. We injected synthesized pigq mRNA into embryos with rps19 knockdown (the DBAS model), and found that the anemia phenotype was rescued, but morphological defects were not, indicating its role in erythropoiesis in zebrafish. These results suggest that impaired translation of erythropoiesis-related and glycan biosynthesis-related genes is implicated in the pathogenesis of DBAS.