Postdoc Center for iPS Cell Research and Application (CiRA), Kyoto University Kyoto, Kyoto, Japan
Abstract: Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a significant decrease in red blood cells and physical abnormalities. DBA results from heterozygous mutations in ribosomal protein (RP) genes, with over 20 causative genetic mutations. However, approximately 40% of the patients do not exhibit these mutations, suggesting the presence of other causative genes or mechanisms. Our previous report confirmed that DBA causative genes are regulated post-translationally in human induced pluripotent stem cells (hiPSCs). We generated and compared hiPSCs derived from DBA patients. RPL5/11 DBA-hiPSCs showed defective differentiation potential in the early mesoderm. Furthermore, although the protein levels of RPs in DBA-hiPSCs were comparable to those in healthy hiPSCs, they decreased during mesodermal differentiation. By knockdown of RPL5 during the differentiation, differentiation defects observed in patient-derived clones were recapitulated. Global protein expression analysis identified ECM-related genes were commonly downregulated during mesodermal differentiation in both patient and knockdown clone-derived cells. These findings suggest that DBA genes undergo different quantity control between hiPSCs and differentiated cells, and the dysregulation of protein levels may occur during developmental processes. This study would propose a novel mechanism for the onset of DBA, and lead to a better understanding of common principles underlying mutation-independent DBA pathogenesis.
