Communicated by Maria Rita Passos-BuenoDiamond-Blackfan anemia (DBA) is an inherited disease characterized by pure erythroid aplasia. Thirty percent (30%) of patients display malformations, especially of the hands, face, heart, and urogenital tract. DBA has an autosomal dominant pattern of inheritance. De novo mutations are common and familial cases display wide clinical heterogeneity. Twenty-five percent (25%) of patients carry a mutation in the ribosomal protein (RP) S19 gene, whereas mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 are rare. These genes encode for structural proteins of the ribosome. A link between ribosomal functions and erythroid aplasia is apparent in DBA, but its etiology is not clear. Most authors agree that a defect in protein synthesis in a rapidly proliferating tissue, such as the erythroid bone marrow, may explain the defective erythropoiesis. A total of 77 RPS19 mutations have been described. Most are whole gene deletions, translocations, or truncating mutations (nonsense or frameshift), suggesting that haploinsufficiency is the basis of DBA pathology. A total of 22 missense mutations have also been described and several works have provided in vitro functional data for the mutant proteins. This review looks at the data on all these mutations, proposes a functional classification, and describes six new mutations. It is shown that patients with RPS19 mutations display a poorer response to steroids and a worse long-term prognosis compared to other DBA patients. Hum Mutat 29(7), [911][912][913][914][915][916][917][918][919][920] 2008.

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Background: Diamond-Blackfan anaemia (DBA) is a rare inherited red cell hypoplasia characterised by a defect in the maturation of erythroid progenitors and in some cases associated with malformations. Patients have an increased risk of solid tumors. Mutations have been found in several ribosomal protein (RP) genes, i.e RPS19, RPS24, RPS17, RPL5, RPL11, RPL35A. Studies in haematopoietic progenitors from patients show that haplo-insufficiency of an RP impairs rRNA processing and ribosome biogenesis. DBA lymphocytes show reduced protein synthesis and fibroblasts display abnormal rRNA processing and impaired proliferation.

The biochemical phenotype of cells affected by ribosomal stress has not yet been studied in detail. Here we report a comparative proteomic analysis of cell lines silenced for the RPS19 gene versus cell lines transfected with scramble shRNA cells performed using the DIGE technology integrated to bioinformatics tools. Importantly, to achieve the broadest possible understanding of the outcome, we carried out two independent DIGE experiments using two different pH ranges, thus, allowing the identification of 106 proteins. Our data revealed the deregulation of proteins involved in cytoskeleton reorganization, PTMs, and translation process. A subset (26.9%) of these proteins is translated from transcripts that include internal ribosome entry site motifs. This supports the hypothesis that during ribosomal stress translation of specific messenger RNAs is altered.