Diamond Blackfan anemia: A paradigm for a ribosome-based disease.

Diamond Blackfan anemia is characterized by a severe hypoplastic anemia and a heterogeneous collection of other clinical features. Approximately 25% of Diamond Blackfan anemia cases are associated with mutations in the gene encoding ribosomal protein S19. The hypothesis presented here ties together molecular and clinical features of the disease, and establishes a conceptual framework for understanding many of the unusual characteristics of a growing number of diseases linked to factors involved in ribosome synthesis. The hypothesis states that ribosomal proteins are expressed in amounts that differ relative to one another in a tissue-specific manner, and that haploinsufficiency for a particular protein may make that protein limiting for ribosome assembly in some tissues, while other tissues remain unaffected. Further, polymorphisms in factors controlling the expression of a particular ribosomal protein gene may alter its expression and expand or contract the number of tissues affected from individual to individual. Support for the hypothesis comes from the observation that promoters in ribosomal protein genes exhibit little conservation and transcription profiling indicates that the absolute amounts of mRNAs for individual ribosomal proteins can vary dramatically relative to one another. Balanced expression of ribosomal proteins is achieved post-translationally, where excess proteins not assembled into ribosomal subunits are often rapidly degraded. The number of ribosomes per cell is therefore determined by the factors that limit assembly. In principle, any essential ribosomal protein could become limiting for assembly if its level of expression falls below a critical threshold. Whether an inactivating mutation in ribosomal protein gene would affect protein synthetic capacity of a tissue would depend on the ratio of the ribosomal protein relative to other ribosomal proteins in that tissue. If the ratio were high, the tissue may not be affected as the level of functional protein may not fall to a point where it becomes limiting for subunit assembly. In contrast, if the ratio were low, an inactivating mutation could make the protein limiting for subunit assembly resulting in a clinical phenotype. Polymorphisms in the myriad of cis- and trans-acting factors, which govern the expression of ribosomal proteins in response to developmental and physiological signals, could act to increase or decrease ribosomal protein expression and thereby impact the profile and severity of clinical phenotypes. Therefore, these factors represent targets for the development of new therapies to treat Diamond Blackfan anemia and other ribosome based diseases.