mRNA translation regulation in Diamond Blackfan Anaemia

Diamond Blackfan Anemia is a bone marrow failure syndrome in which patients lack erythroid precursor cells in the bone marrow. Therefore, it is also designated as pure red cell aplasia, as other hematological indices are at normal levels. Around half of DBA patients bear an autosomal dominant mutation in one of the ribosomal protein genes which leads to decreased cellular ribosomal content. How mutations in such general proteins can result in an erythroid restricted phenotype is as yet unknown. In this thesis we aimed to elucidate the pathological mechanisms of erythroid failure in DBA. We hypothesized, that decreased ribosomal content in erythroid precursor cells could cause a decrease in the translation of important transcripts. For this purpose, we set up shRNA mediated knockdown of ribosomal proteins in proerythroblasts followed by translational profiling. After we have confirmed that translational deregulation of erythroid-specific transcripts occurs in DBA patients too, we further investigated their function. We aimed to characterize erythroid in vitro phenotype of Bag1 knockout mice and investigate the molecular role of Bag1 in the unfolded protein response. Further, we set out to delineate the function of Csde1 in translational regulation during erythropoiesis. In summary, we identified novel genes that are subject to selective translation and important for erythropoiesis. Reduced translation of the encoded transcripts may contribute to the pathophysiological mechanism by which mutations in ribosomal proteins in Diamond Blackfan Anemia patients cause the decrease in erythroid expansion and anemia.

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