Ribosomal protein mutations in Diamond-Blackfan anemia: might they operate upstream from protein synthesis?

Abstract

The inherited bone marrow failure syndromes are clinically distinct but share some common features. Difficult to treat and typified by a poor prognosis, their pathogenesis is unknown. Recent findings that some patients with the erythroblastopenia Diamond-Blackfan anemia (DBA) have mutations in ribosomal proteins have led to the idea that this and perhaps other bone marrow failure disorders result from an inadequate supply of normally functioning ribosomes. According to this hypothesis, an insufficiency of the protein synthetic capacity limits the replicative potential of cells, with the DBA disease phenotype in particular arising from a block of one or more of the two to four critical, temporally compressed cell divisions in the differentiation program of the erythroid lineage in the fetal liver and the postnatal bone marrow. Here I propose an alternative (but not mutually exclusive) hypothesis centered on nucleoli: the specialized intranuclear domains within which ribosomes are assembled. It was recently discovered that the nucleoli contain cell cycle machinery in close proximity to nascent ribosomes. Although mutations in ribosomal proteins might be expected to negatively influence the cell's protein synthetic capacity, I suggest it is also possible that the DBA mutations directly affect the nucleolus to destabilize or otherwise deregulate the coresident cell cycle machinery. This hypothesis envisions that the ribosomal protein mutations discovered in DBA act upstream from ribosome assembly by interfering with the staging of cell cycle progression machinery in the nucleolus, in a pretranslational mode of pathogenesis.