Ribosomopathies: how a common root can cause a tree of pathologies.

Nadia Danilova,Hanna T Gazda

doi:10.1242/dmm.020529

Abstract

ABSTRACTDefects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. Ribosomes are composed of ribosomal proteins (RPs) and ribosomal RNA (rRNA). RPs and multiple other factors are necessary for the processing of pre-rRNA, the assembly of ribosomal subunits, their export to the cytoplasm and for the final assembly of subunits into a ribosome. Haploinsufficiency of certain RPs causes DBA, whereas mutations in other factors cause various other ribosomopathies. Despite the general nature of their underlying defects, the clinical manifestations of ribosomopathies differ. In DBA, for example, red blood cell pathology is especially evident. In addition, individuals with DBA often have malformations of limbs, the face and various organs, and also have an increased risk of cancer. Common features shared among human DBA and animal models have emerged, such as small body size, eye defects, duplication or overgrowth of ectoderm-derived structures, and hematopoietic defects. Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways. The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies. Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

Highlights

Diamond-Blackfan anemia (DBA) is a congenital syndrome associated with anemia, physical malformations and cancer (Halperin and Freedman, 1989; Vlachos et al, 2012)
Activation of the innate immune system The upregulation of genes involved in interferon and TNFα signaling has been reported in red blood cell progenitors and in fibroblasts obtained from DBA patients (Avondo et al, 2009; Gazda et al, 2006a), as well as in Rpl11-deficient zebrafish (Danilova et al, 2011)
DBA studies have stimulated the field of ribosome biogenesis, resulting in a better understanding of the mechanisms of pre-ribosomal RNA (rRNA) processing and of ribosome subunit formation

Summary

Introduction

Diamond-Blackfan anemia (DBA) is a congenital syndrome associated with anemia, physical malformations and cancer (Halperin and Freedman, 1989; Vlachos et al, 2012). Deficiency of most other RPs that are mutated in DBA, both from the small and the large ribosomal subunits, affects pre-rRNA processing in a unique way, leading to the accumulation of different rRNA precursors and disruption of ribosome biogenesis at different steps (Robledo et al, 2008).

Results

Conclusion