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Review
. 2014 Jun 3:5:158.
doi: 10.3389/fgene.2014.00158. eCollection 2014.

Transfer RNA and human disease

Affiliations
Review

Transfer RNA and human disease

Jamie A Abbott et al. Front Genet. .

Abstract

Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

Keywords: Usher syndrome Type IIIB; aminoacyl-tRNA synthetase; localized translation; mitochondrial disease; neurodegenerative disease; tRNA.

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Figures

Figure 1
Figure 1
Structural analysis of mitochondrial tRNA and disease causing mutations. Cloverleaf structure of mt-tRNAHis and mt-tRNAIle. Mutations discussed in this review that cause neurosensory disease (blue), cardiomyopathy (red), MELAS and MERRF (green), and other pathological reported mutations not discussed in this review (gray). The 3D mt-tRNAHis and mt-tRNAIle models were generated using ModeRNA (Rother et al., 2011) of human mt-tRNA sequence (Sprinzl and Vassilenko, 2005) alignments. Sequences were fit to structural tRNA templates PDB: 1QTQ for mt-tRNAHis model and PDB: 1QUZ for mt-tRNAIle.
Figure 2
Figure 2
Transfer RNA interactions and associated diseases. Cellular pathways of tRNA and interacting proteins and enzymes. Diseases discussed in this review are italicized in red. Figure was generated using BioDraw Ultra 12.0. Disease abbreviations: Charcot-Marie-Tooth disease (CMT), pulmonary veno-occlusive disease (PVOD), pontocerebellar hypoplasia (PCH). Enzyme abbreviations: AARS, aminoacyl-tRNA synthetase; CLP1, cleavage and polyadenylation factor I subunit 1; TSEN, tRNA-splicing endonuclease complex; IFIT, interferon-induced tetratricopeptide repeat; GCN2, general control nonderepressible 2.

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