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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

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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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.

Mentions: The human genome contains approximately 500 tRNA genes, including gene duplications (Lowe and Eddy, 1997; Schattner et al., 2005). However, there are only 61 anticodons specified by the triplet code, so many of these identified tRNA genes share the same anticodon but differ in sequence elsewhere. Remarkably, a human disease that is linked to a mutation in a cytoplasmic tRNA has not yet been reported, and this may be a direct result of the presence of multiple paralogs of the gene encoding each cytoplasmic tRNA molecule. The tRNA for each anticodon, save a single gene for tRNATyr (ATA), is encoded by as many as 32 paralogous genes (Chan and Lowe, 2009). The process of generating each mature tRNA is a complex sequence of events that includes gene transcription, splicing, 5′ and 3′ end processing, CCA addition, transportation, and aminoacylation (Hopper et al., 2010). Errors in this sequence arising from mutations in the genes encoding the enzymes that bind and process cytoplasmic tRNA molecules are known, and account for a number of reported diseases. Furthermore, a growing body of literature suggests that tRNA molecules possess previously unrecognized biological functions in eukaryotes which are not fully understood (Phizicky and Hopper, 2010), and that may be perturbed by disruptions of the tRNA-protein interaction. Some of these biological functions include regulation of cellular apoptosis (Mei et al., 2010; Hou and Yang, 2013). See Figure 2 for a schematic overview.


Transfer RNA and human disease.

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

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

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

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.
Mentions: The human genome contains approximately 500 tRNA genes, including gene duplications (Lowe and Eddy, 1997; Schattner et al., 2005). However, there are only 61 anticodons specified by the triplet code, so many of these identified tRNA genes share the same anticodon but differ in sequence elsewhere. Remarkably, a human disease that is linked to a mutation in a cytoplasmic tRNA has not yet been reported, and this may be a direct result of the presence of multiple paralogs of the gene encoding each cytoplasmic tRNA molecule. The tRNA for each anticodon, save a single gene for tRNATyr (ATA), is encoded by as many as 32 paralogous genes (Chan and Lowe, 2009). The process of generating each mature tRNA is a complex sequence of events that includes gene transcription, splicing, 5′ and 3′ end processing, CCA addition, transportation, and aminoacylation (Hopper et al., 2010). Errors in this sequence arising from mutations in the genes encoding the enzymes that bind and process cytoplasmic tRNA molecules are known, and account for a number of reported diseases. Furthermore, a growing body of literature suggests that tRNA molecules possess previously unrecognized biological functions in eukaryotes which are not fully understood (Phizicky and Hopper, 2010), and that may be perturbed by disruptions of the tRNA-protein interaction. Some of these biological functions include regulation of cellular apoptosis (Mei et al., 2010; Hou and Yang, 2013). See Figure 2 for a schematic overview.

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