MOLECULAR BASIS OF DIAMOND-BLACKFAN ANEMIA

Diamond-Blackfan Anemia (DBA) is a congenital defect of red cell maturation, characterized by severe anemia appearing in early infancy. A resolutive treatment is not available for most cases: many patients require lifelong blood transfusion with iron chelation or stem cell transplantation. Life expectancy is drastically reduced in these patients. The disease is genetically heterogeneous: 25% of patients have mutations in ribosomal protein S19 (RPS19), but its role in red cell maturation has not been elucidated yet; rare patients carry mutations in another RP (RPS24). The genes responsible for the other cases are still unknown, but recent data suggest that DBA is due to a general defect of protein synthesis. The aim of our proposal is to identify the role of RPS19 in the pathogenesis of DBA. We feel that the identification of this role will help to understand also the pathogenesis of the forms not due to mutations in the RPS19 gene. We have worked out a tentative hypothesis that takes into account data published during this year from our group and from others and preliminary data from our laboratory. We feel that DBA is due to a defect in translation of specific mRNAs. The project will follow two main research steps: 1) identification of transcripts interacting with RPS19. Preliminary data from our laboratory show that RPS19 interacts with several transcripts. We will also address the characterization of the interaction between RPS19 and PIM1, a protein that we have demonstrated to bind RPS19. The function of RPS19 may be regulated by PIM1. 2) We will also analyse some aspects still uncharacterised concerning the metabolism of RPS19 and the translation capacity in cells from DBA patients and experimental model systems. The outcome of our investigation may reveal important aspects of the molecular basis of DBA as well as of erythropoiesis and new aspects of translation. It might also suggest new treatment solutions.