Review Article | Published:

Translation deregulation in human disease


Advances in sequencing and high-throughput techniques have provided an unprecedented opportunity to interrogate human diseases on a genome-wide scale. The list of disease-causing mutations is expanding rapidly, and mutations affecting mRNA translation are no exception. Translation (protein synthesis) is one of the most complex processes in the cell. The orchestrated action of ribosomes, tRNAs and numerous translation factors decodes the information contained in mRNA into a polypeptide chain. The intricate nature of this process renders it susceptible to deregulation at multiple levels. In this Review, we summarize current evidence of translation deregulation in human diseases other than cancer. We discuss translation-related diseases on the basis of the molecular aberration that underpins their pathogenesis (including tRNA dysfunction, ribosomopathies, deregulation of the integrated stress response and deregulation of the mTOR pathway) and describe how deregulation of translation generates the phenotypic variability observed in these disorders.

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The authors thank E. Shoubridge, D. Ruggero, A. Shimamura, E. Storkebaum and S. J. Baserga for insightful discussions and input on this Review.

Author information

S.T. and A.K. researched data for the article and made substantial contributions to the discussion of content; S.T., A.K., M.B.M. and N.S. wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Soroush Tahmasebi or Nahum Sonenberg.

Supplementary information

  1. Supplementary table 1


Aminoacyl-tRNA synthetases

(ARSs). Enzymes that catalyse the addition of an amino acid to the appropriate tRNA.


(τm5U). A post-transcriptional modification of uridine at the wobble position of the mammalian mitochondrial tRNAs for Leu (UUR) and Trp.


A formylated form of the elongating Met-tRNAMet that is used as an initiator of tRNA in mammalian mitochondria.


(t6A). A universal tRNA modification at position 37 of tRNAs that decode ANN codons.


A condition in diploid organisms where one gene copy is inactivated by mutation and the activity of the remaining copy is insufficient to maintain normal function.

Clonal dominance

A condition in which a single clone of haematopoietic stem cells (HSCs) supersedes the other HSC clones.

Overgrowth syndromes

A group of genetic diseases that are manifested as abnormal growth of the whole body or of body parts.

Codon usage

The frequency with which a specific codon is used in the coding sequence of a mRNA or set of mRNAs.

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Further reading

Fig. 1: Defects in tRNAs, aminoacyl-tRNA synthetases and translation elongation factors.
Fig. 2: Human diseases linked to mitochondrial or cytosolic tRNA modifications.
Fig. 3: A simplified overview of ribosome biogenesis.
Fig. 4: Integrated stress response-related diseases.
Fig. 5: Human diseases linked to the mTOR complex 1 pathway.
Fig. 6: Proposed mechanisms for tissue specificity of diseases caused by deregulation of protein synthesis.