Ribosomopathies: There’s strength in numbers

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Science  03 Nov 2017:
Vol. 358, Issue 6363, eaan2755
DOI: 10.1126/science.aan2755

Molecular mechanisms behind ribosomopathies

Ribosomopathies are t issuespecific disorders that result from mutations in ribosomal proteins or ribosome biogenesis factors. Such disorders include Diamond-Blackfan anemia, isolated congenital asplenia, and Treacher Collins syndrome. Mills and Green review the underlying mechanisms of tissue-specific defects in these and related disorders. Because ribosomes are central to all cellular life, it is puzzling why mutations in components of the ribosome disproportionately affect certain tissues. The authors suggest that ribosome homeostasis is an overarching and simplifying principle that governs the sensitivity of specific cells and tissue types to mutation in components of the translational machinery.

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Structured Abstract


Ribosomopathies are a heterogeneous group of human disorders that are in some cases known, and in other cases suspected, to result from ribosome dysfunction. This group broadly comprises two categories: (i) disorders caused by single-copy mutations in specific ribosomal proteins, and (ii) disorders associated with defects in ribosome biogenesis factors. The phenotypic patterns among different ribosomopathies in both categories are divergent but do tend to share some overlapping features. These include effects on bone marrow–derived cell lineages and skeletal tissues. These common tissue specificities of the different ribosomopathies are challenging to reconcile with the ubiquitous requirement for ribosomes in all cells.


Several models have been advanced to explain how the dysfunction of the protein synthesis machinery is so variably expressed at the phenotypic level. An increasing number of studies in models of distinct ribosomopathies have revealed that “ribosomal stress” signals converge on the p53 signaling pathway in affected cells and tissues. In these models, a key consequence of ribosome dysfunction is cell- and tissue type–restricted activation of p53-dependent cell cycle arrest and apoptosis. However, the specific translational events upstream of p53 activation that lead to some cells being affected, with others being spared, are unknown.

We review evidence relating to two hypotheses that have been proposed to explain such tissue-specific effects of ribosome dysfunction. One hypothesis is that ribosome dysfunction (or deficiency) can affect global and messenger RNA (mRNA)–specific translational control, and that certain specific cells or tissues may be more vulnerable to ribosome dysfunction. A critical feature of this view is that mRNAs are variably dependent on cellular ribosome concentration, with more poorly initiated mRNAs being typically more sensitive to perturbations in ribosome concentration or function. Several recent studies suggest that the sensitivities of certain tissues to ribosomopathies, including reticuloctyes and platelets, may be related to differences in core processes of translation in these cells related to ribosome recycling and rescue. Perturbations in these processes will have a great impact on ribosome homeostasis and thus on broad aspects of gene expression. Related studies in the brain have revealed disease phenotypes in genetic backgrounds with deficiencies in ribosome rescue and in a specific neuronal transfer RNA. Together, these molecular insights provide a new perspective on ribosomopathies and their tissue specificities, while also raising a number of important questions to pursue.

The other hypothesis is that ribosomes from different tissues may have different compositions of core or more loosely associated proteins and posttranslational modifications, and that this heterogeneity could be critical to the translation of specific mRNAs. This is referred to as the “specialized” ribosome hypothesis. We argue that while such heterogeneity in ribosome composition likely exists in different tissues, such complex explanations may not be needed to explain the differences in gene expression that result from losses of specific ribosomal proteins. It is simpler to hypothesize that differences in mRNA-specific rates of initiation and changes in ribosome concentration can adequately explain much (if not all) of the diversity of gene expression changes in different tissues as a result of ribosomal mutations.


A cohesive mechanistic model connecting dysfunction of the ribosome to the specific phenotypic consequences observed in ribosomopathies remains a challenging goal. For example, it is inherently difficult to assess the function of particular ribosomes in a cell, and thus to differentiate among various models to explain the impacts of ribosome deficiencies on gene expression. Further biochemical analyses of the fundamental processes underlying the cellular response to protein synthesis dysfunction, refinements in cellular and animal models of ribosomopathies, and greater dialogue between clinical and basic scientists will all be important to extend our current understanding.

Ribosome concentration drives mRNA-specific effects on translation.

The translation rate varies as a function of cellular ribosome concentration and mRNA-specific initiation rates (heat map, left); a scatterplot model of ribosome footprinting data (right) shows how ribosome deficiency would be predicted to have varying effects on different mRNAs. The black, gray, and orange boxes define groups of mRNAs of similar initiation efficiencies as they respond to changes in ribosome concentration (as represented by the same colors at right).


Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA–specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.

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