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.