Translation matters: protein synthesis defects in inherited disease

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Abstract
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.

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