[Molecular mechanisms underlying the pathology of Diamond-Blackfan anemia].

Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome, characterized by red blood cell aplasia. Macrocytic anemia is a prominent feature of DBA but the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 40% of affected patients. DBA is associated with single, monoallelic, inactivating mutations in ribosomal protein (RP) genes. In DBA, mutations or large deletions in RP genes include RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPL5, RPL11, RPL26 and RPL35A. These mutations have been reported in up to 60% of DBA patients. To date, no known pathogenic mutations have been found in the remaining patients. In an effort to identify new mutations responsible for DBA, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions in our first screening and identified a de novo splicing error mutation in RPL27 and a frameshift deletion in RPS27 in sporadic patients with DBA. In vitro knockdown of the gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. In this report, we also discuss current knowledge regarding pathways from the impairment of ribosomal biogenesis to the pathology of DBA.