THE DIAGNOSIS AND PATHOGENESIS OF DIAMOND-BLACKFAN ANEMIA: VALIDATION OF A NOVEL RPL5 MUTATION
Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome mostly caused by heterozygous mutations in ribosomal proteins, which play an essential role in protein translation and usually results in a severe macrocytic red blood cell (RBC) cytopenia along with congenital malformations. How a defect in the ubiquitous ribosome can lead to a specific failure of RBC formation is not well understood and requires further study. In this case study, we present a child with characteristic features of DBA along with a novel RPL5 mutation and concomitant SLX4 mutation. In this patient, the RPL5 mutation was discovered by genomic analysis performed by INVITAE labs. We are currently in the process of validating this novel mutation by polysome analysis in the laboratory, which we expect will reveal a decrease in large ribosome subunits as well as a decrease in total ribosome content. This case is also the impetus for a future study in which stem/progenitor cells will be isolated from patients with known or suspected DBA to confirm the diagnosis by DNA, RNA, protein, or polysome analysis. The study will also look at cell phenotypes of DBA patients vs normal patients vs. silent carriers who have a DBA mutation but no apparent hematological phenotype. Once an underlying aberrant pathway is identified, compounds targeting these pathways will be tested in vitro using cells from DBA patients to determine whether they correct the aberrant phenotype.