Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Ribosome Protein Mutations can cause Tissue-Specific human disease


Science 23 August 2013: Vol. 341 no. 6148 pp. 849-850

Mysterious Ribosomopathies

Kathleen L. McCann1, Susan J. Baserga

1Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

2Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.

3Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.


Ribosomes are absolutely essential for life, generating all cellular proteins required for growth. The prevailing thought for many years was that mutations in ribosomal proteins or ribosome assembly factors would be lethal to developing embryos. Complete loss of any single ribosomal protein often leads to embryonic lethality in mice. Yet, mutations in ribosomal proteins or ribosome assembly factors result in a puzzling phenomenon—a specific mutation can affect a specific cell type and cause a tissue-specific human disease. What accounts for this tissue proclivity has been a mystery. Why do defects in a macromolecule as ubiquitous and essential as the ribosome cause diseases—ribosomopathies—only in select tissues?

Eukaryotic ribosomes are large, intricate cellular machines that translate messenger RNA (mRNA) into protein. They comprise four different ribosomal RNAs (rRNAs; 18S in the small subunit and 28S, 5.8S, and 5S in the large subunit), as well as 80 ribosomal proteins. More than 200 assembly factors and small RNAs are needed to synthesize ribosomes in the nucleolus. Some of the structural components also control the processing of precursor ribosomal RNA (pre-rRNA), assembly of the ribosomal subunits, and the translation process itself. Over the past 15 years, mutations in ribosomal proteins or ribosome biogenesis factors have been found in patients with varying diseases.

One explanation is that the composition of ribosomes may be different in different cell types, which could account for the various effects of ribosomal protein haploinsufficiency. This idea may contradict the notion that ribosomes are monolithic machines, but it is not completely unfounded. Surprisingly, the reduction of a specific ribosomal protein can lead to changes in the spectrum of translated mRNAs without affecting overall protein synthesis.

In some cases, mutations that disrupt ribosome assembly can cause the nucleolar stress response in some cell types. This response involves increased synthesis of the protein p53. This tumor suppressor protein arrests cell division in response to such stress, which leads to programmed cell death (apoptosis).

Mutations in ribosomal proteins and assembly factors confer a broad clinical spectrum. Although the mechanisms underlying the tissue proclivity in ribosomopathies are yet to be defined, these disorders do make it increasingly clear that the days of thinking of ribosomes as unchanging monoliths are coming to an end.

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