Ontogeny as a critical determinant of DBA sensitivity in red blood cell.

In this project FRRB finances Partner number 1, the Coordinator: San Raffaele – Telethon Institute for Gene Therapy (SR-TIGET), Milano. The Principal Investigator responsible of the project is Dr. Andrea Ditadi.

Pathology of interest:  Diamond-Blackfan Anemia (DBA)
Area of research:  Ribosomopathies
Start date:  01/09/2020
End date:  31/08/2023
Funding:  € 352.400,00
Project partners:
  • San Raffaele – Telethon Institute for Gene Therapy (SR-TIGET), Italy – leading partner
  • Centre de Biologie Intégrative (CBI), France
  • Department of Molecular Genetics, Weizmann Institute of Science, Israel
  • Lund Stem Cell Center, Lund University, Sweden
  • Medical Faculty of Palacky University Olomouc, Czech Republic


Mutation in the component ribosomal proteins can cause diseases, termed ribosomopathies, of which the best known is Diamond-Blackfan Anemia (DBA), which affects the production of red blood cells (RBCs).

RBCs are the most abundant cell type in the body and an essential component for life. Thus, RBCs are constantly produced throughout embryonic, fetal and postnatal life. However, DBA patients present hematological symptoms and die from anemia if not treated only after birth, indicating that only RBCs produced postnatally are sensitive to DBA mutations.

Our goal is to understand what determines the difference in sensitivity to a DBA mutation across the different RBCs produced before and after birth. We hypothesize that impaired RBC production observed after birth may be caused by altered ribosome availability or by the acquisition of a developmental-specific ribosome repertoire (i.e. a “ribosome code”) postnatally.

To distinguish between these possibilities, we will use human embryonic stem cells haploinsufficient for RPS19, the most common mutation causing erythroid aplasia in DBA. Using this innovative DBA disease model, we propose to systematically study how defects in ribosome synthesis and/or mRNA translation have varying impacts during the differentiation of the erythroid lineage across the three developmental programs and how the most common DBA mutation affects gene expression as well as ribosome maturation in all three waves of erythropoiesis. We will use this information to identify key differences in postnatal erythropoiesis relative to prenatal erythropoiesis and see if we can rescue postnatal RBCs from the phenotypic defects associated with DBA.

In summary, this genetically tractable system will allow us to address the dynamics and potential functional role of specialized ribosomes during RBC development. Our combined expertise will identify lineage-specific “translational targets”, which will be tested as novel targeted therapeutic avenues for patients affected by DBA.


For more information on the transnational projects funded under the EJP RD Call JTC 2019 visit the following page