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  • Review Article
  • Published:

Translation matters: protein synthesis defects in inherited disease

Nature Reviews Genetics volume 8, pages 711–723 (2007)Cite this article

Key Points

  • Many genetic diseases are now known to arise from defects that affect the protein synthesis machinery or its control.

  • Given the essential role that protein synthesis is thought to have in all cell types and tissues, the observed tissue specificity of many of the diseases that are associated with defects in translation is surprising. Elucidation of the disrupted processes in affected cells indicates that several factors involved in protein synthesis, often regarded as mere housekeeping proteins, have additional non-canonical functions.

  • Some diseases are due to mutations that affect the translation of specific mRNAs. Such mutations are outside the coding region of the mRNA, and do not affect the sequence of the protein, but instead impair the sophisticated control mechanisms that govern how much of the protein is synthesized.

  • Translation factors are non-ribosomal proteins that assist the ribosome during mRNA translation. Mutations in them can cause disease, such as the neurodegeneration that results from mutations in the initiation factor eIF2B ('vanishing white matter').

  • Translation factors are regulated by protein kinases, which allow translation to be rapidly fine-tuned. Mutations in one of them (pancreatic endoplasmic reticulum-resident kinase (PERK)) give rise to Wolcott–Rallison disease, which is characterized by infantile-onset diabetes.

  • Mutations in proteins of the ribosome itself also cause disease, probably by interfering with ribosome biogenesis. Examples include Diamond–Blackfan anaemia and bone marrow failure (X-linked dyskeratosis congenita).

  • Amino-acyl-tRNA synthetases ensure that the right amino acid is attached to the relevant tRNA. Mutations that affect their accuracy or localization lead to neurological disorders such as Charcot–Marie–Tooth (CMT) disease.

  • Mitochondria have their own distinct protein synthesis machinery, several components of which are encoded by mitochondrial DNA (mtDNA). The small mitochondrial genome is well studied and a range of conditions are known to arise from mutations in mitochondrial genes that encode tRNAs. Heteroplasmy has a key role in determining the exact phenotype and the severity of these disorders

  • All the proteins involved in mitochondrial translation are encoded by nuclear genes. Mutations in genes for mitochondrial amino-acyl-tRNA synthetases, ribosome proteins, and mitochondrial elongation factors lead to different diseases.

Abstract

The list of genetic diseases caused by mutations that affect mRNA translation is rapidly growing. Although protein synthesis is a fundamental process in all cells, the disease phenotypes show a surprising degree of heterogeneity. Studies of some of these diseases have provided intriguing new insights into the functions of proteins involved in the process of translation; for example, evidence suggests that several have other functions in addition to their roles in translation. Given the numerous proteins involved in mRNA translation, it is likely that further inherited diseases will turn out to be caused by mutations in genes that are involved in this complex process.

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Figure 1: Protein synthesis.
Figure 2: Translation initiation.
Figure 3: Mutations in 5′ untranslated (5′ UTR) regions.

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Acknowledgements

We thank E. Jan for his careful reading of this manuscript. Work in the authors' laboratories on mRNA translation and human health is supported by the Canadian Institutes for Health Research, The Multiple Sclerosis Research Society of Canada and the Heart & Stroke Foundation of British Columbia and the Yukon (CGP), and by the Dutch Organization for Scientific Research, W. M. Phelps Stichting and the Optimix Foundation for Scientific Research (GCS, MSvdK).

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Authors and Affiliations

  1. Department of Child Neurology/Center for Neurogenomics and Cognitive Research, Vrije Universiteit Medical Center, De Boelelaan 1117, Amsterdam, 1081HV, The Netherlands

    Gert C. Scheper & Marjo S. van der Knaap

  2. Department of Biochemistry & Molecular Biology and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Christopher G. Proud

Authors
  1. Gert C. Scheper
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  2. Marjo S. van der Knaap
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Correspondence to Christopher G. Proud.

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Related links

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DATABASES

OMIM

Alzheimer disease

anauxetic dysplasia

cartilage-hair hypoplasia

Diamond–Blackfan anaemia

LBSL

leukoencephalopathy with vanishing white matter

MELAS

MLASA

Parkinson disease

Shwachman–Diamond disease

Wolcott–Rallison syndrome

X-linked Charcot–Marie–Tooth disease

X-linked dyskeratosis congenita

FURTHER INFORMATION

Christopher G. Proud's homepage

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Mitomap

Office of Rare Diseases

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Glossary

A-site

One of three binding sites for tRNAs on the ribosome, the acceptor site (A-site) is the one into which amino-acyl-tRNAs are recruited to decode the next codon of the mRNA.

5′ cap structure

A modified nucleotide attached to the 5′ end of precursor mRNA within the nucleus. It has key roles in the function of the mRNA, for example, in its translation.

Methionyl-tRNA

A tRNA to which a methionine residue is attached: a specific 'initiator' methionyl-tRNA recognizes the AUG start codon and provides the first amino acid of the new polypeptide.

Eukaryotic initiation factors

Proteins involved in the first stage of mRNA translation.

Telomerase

An enzyme that modifies the ends of eukaryotic chromosomes.

Telomere erosion

A decrease in the number of repeat sequences at the ends of chromosomes.

Kozak consensus sequence

gccgcc(A/G)ccAUGG: the most favourable sequence to serve as translational start site (AUG, underlined). The purine at position −3 from the AUG start codon and the 'G' at +1 are the most important determinants.

Pseudouridylation

A post-transcriptional nucleotide modification found in RNAs.

Trans-acting factors

RNA-binding proteins that regulate translation of specific mRNAs.

Ribosomal proof reading

Accurate recognition of the codons that enter the ribosomal A-site to prevent misincorporation errors during polypeptide synthesis.

Taurine

An amino-sulphonic acid that can modify the wobble position of mitochondrial tRNAs.

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Scheper, G., van der Knaap, M. & Proud, C. Translation matters: protein synthesis defects in inherited disease. Nat Rev Genet 8, 711–723 (2007). https://doi.org/10.1038/nrg2142

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