Rps19 R67∆ mutation creates a model of Diamond-Blackfan anemia and reveals downstream mediators of p53 pathway.

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 S19 (Rps19), a part of the 40S ribosomal subunit. We developed a transgenic model harboring deletion of conserved Arg 67 in RPS19, which is the site of post-translational modification by protein-arginine methyl transferase family and could show that the defect in Rps19 causes phenotype in perfect overlap with the DBA including hematologic dysfunctions, hypotrophy, intrinsic anemia, severe craniofacial, skeletal, urogenital, cardiovascular, and cerebral abnormalities leading to premature lethality during the adolescence of the mouse. This DBA mouse model exhibited activation of the Trp53 signaling pathway in hematopoietic stem cells (HSCs) leading to reduced erythroid lineage development. Competitive transplantation assays using Rps19-deficient bone marrow cells confirmed that HSCs and their progeny lineages were affected while their differentiation was rescued after inactivation of the tumor suppressor Trp53 showing that the development of the DBA phenotype significantly involves non-canonical components of the p53 signaling pathway in the etiopathogenesis of DBA with the Rps19R67∆ mutation leading to the disrupted hematopoietic hierarchy starting at the stage of short-term repopulating stem cells. The activated p53 pathway was mediated by downstream molecules Zmat3, Phlda3, and Eda2r, whose overall function in the pathology of DBA involve erythroid differentiation blockade coupled with cell proliferation and survival disruption. To conclude, the new DBA model represents a powerful tool for exploring new therapeutic options for DBA.