Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome accompanied by cardiovascular, skeletal, and urogenital abnormalities. Most of the affected individuals carry mutations in ribosomal proteins, including RPS19, a component of the 40S ribosomal subunit. We developed a transgenic Rps19 mouse model harboring a deletion of conserved R67 that displays a variable phenotype ranging from mild hematopoietic defects to severe anemia and a set of other skeletal, muscular, and cardiac abnormalities with shorter survival. This mouse model exhibited an activation of the p53 signaling pathway in red blood cell committed hematopoietic stem and progenitor cells, affecting erythroid lineage development. Competitive transplantation assays using Rps19 R67∆ bone marrow progenitor cells confirmed that short-term repopulating hematopoietic stem cells (HSCs) and their progenitor lineages were affected, while their differentiation was rescued after deletion of the tumor suppressor Trp53. Rps19 R67∆ mutation leads to pre-ribosomal RNA (pre-rRNA) accumulation coupled with activation of p53, even at relatively immature hematopoietic stages. In conclusion, we present a mouse model that represents a powerful tool for exploring new therapeutic options for the treatment of ribosomal disorders, including DBA.

Animal Research Centre Ulm University Ulm Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Anatomy and Animal Health School of Veterinary Medicine Universitat Autònoma de Barcelona Bellaterra Spain

Laboratory of Cancer Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Haematooncology and Stem Cells Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec 1st Faculty of Medicine Charles University Prague Czech Republic

Laboratory of Transgenic Models of Disease Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

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