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Transfer RNA and human disease.

Abbott JA, Francklyn CS, Robey-Bond SM - Front Genet (2014)

Bottom Line: Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes.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.We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Medicine, University of Vermont Burlington, VT, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: Other mt-tRNA mutations associated with MELAS and MERRF phenotypes have been isolated in the gene encoding mt-tRNAHis (Figure 1). In the first reports, the mutation was found to be a heteroplasmic G12147A substitution (Melone et al., 2004; Taylor et al., 2004), and analysis of muscle biopsy samples revealed deficiency in cytochrome c oxidase (COX). The G12147A mutation in the D-arm of the mt-tRNAHis molecule would be expected to alter tRNA folding and abundance, leading to a specific decrease in the his-rich COXIII polypeptide, as well as a general decrease in mitochondrial protein synthesis. Additionally, a homoplasmic A12146G mutation was identified in another MELAS patient (Calvaruso et al., 2011). As in the previous example, an analysis of cybrid cells and patient muscle biopsy samples showed that deficiencies in various respiratory chain complexes enzymes were linked to the mt-tRNAHis mutation.


Transfer RNA and human disease.

Abbott JA, Francklyn CS, Robey-Bond SM - Front Genet (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042891&req=5

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.
Mentions: Other mt-tRNA mutations associated with MELAS and MERRF phenotypes have been isolated in the gene encoding mt-tRNAHis (Figure 1). In the first reports, the mutation was found to be a heteroplasmic G12147A substitution (Melone et al., 2004; Taylor et al., 2004), and analysis of muscle biopsy samples revealed deficiency in cytochrome c oxidase (COX). The G12147A mutation in the D-arm of the mt-tRNAHis molecule would be expected to alter tRNA folding and abundance, leading to a specific decrease in the his-rich COXIII polypeptide, as well as a general decrease in mitochondrial protein synthesis. Additionally, a homoplasmic A12146G mutation was identified in another MELAS patient (Calvaruso et al., 2011). As in the previous example, an analysis of cybrid cells and patient muscle biopsy samples showed that deficiencies in various respiratory chain complexes enzymes were linked to the mt-tRNAHis mutation.

Bottom Line: Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes.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.We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Medicine, University of Vermont Burlington, VT, USA.

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.

No MeSH data available.


Related in: MedlinePlus