MOLECULAR BASIS OF DIAMOND-BLACKFAN ANEMIA

Diamond Blackfan Anemia (DBA, OMIM No. 105650) is a congenital defect of red cell maturation, characterized by severe anemia appearing in early infancy and associated with physical abnormalities in 30% of cases. Diagnosis is difficult and a resolutive treatment is not available for most cases: many patients require lifelong blood transfusion with iron chelation. 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; the genes responsible for the other cases are still unknown. The aims of our proposal are: 1) to identify the genes responsible for other forms of DBA by analysing the inheritance of polymorphic markers of the genome (Genome Wide Search) in families with multiple affected children; 2) to ascertain the role of RPS19 in erythropoiesis by identifying proteins able to interact with RPS19 (Yeast Two Hybrid System); 3) to investigate the effect of mutations in RPS19 on the synthesis and function of ribosome in cells isolated from DBA patients; 4) to develop methodologies for the identification of molecules involved in other putative ribosome pathologies, including the forms of DBA not due to RPS19. Parts 1 and 2 will be performed in the PI laboratory, whereas parts 3 and 4 will be performed in the laboratory of Partner 1. Preliminary results obtained in all the reported lines of investigation are promising. The outcome of our investigation will increase the knowledge of the molecular mechanisms involved in DBA and might enable to define new therapeutic strategies. The identification of the genes responsible for the forms not due to RPS19 (75%) will offer the means for prenatal diagnosis, carrier detection and molecular diagnosis in these forms.