1932

Abstract

Transfer RNAs (tRNAs) decode messenger RNA codons to peptides at the ribosome. The nuclear genome contains many tRNA genes for each amino acid and even each anticodon. Recent evidence indicates that expression of these tRNAs in neurons is regulated, and they are not functionally redundant. When specific tRNA genes are nonfunctional, this results in an imbalance between codon demand and tRNA availability. Furthermore, tRNAs are spliced, processed, and posttranscriptionally modified. Defects in these processes lead to neurological disorders. Finally, mutations in the aminoacyl tRNA synthetases (aaRSs) also lead to disease. Recessive mutations in several aaRSs cause syndromic disorders, while dominant mutations in a subset of aaRSs lead to peripheral neuropathy, again due to an imbalance between tRNA supply and codon demand. While it is clear that disrupting tRNA biology often leads to neurological disease, additional research is needed to understand the sensitivity of neurons to these changes.

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2023-10-16
2024-10-15
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Literature Cited

  1. Abbasi-Moheb L, Mertel S, Gonsior M, Nouri-Vahid L, Kahrizi K et al. 2012. Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am. J. Hum. Genet. 90:847–55
    [Google Scholar]
  2. Akashi H. 1994. Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy. Genetics 136:927–35
    [Google Scholar]
  3. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A et al. 2003. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72:1293–99
    [Google Scholar]
  4. Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M et al. 2006. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J. Neurosci. 26:10397–406
    [Google Scholar]
  5. Antonellis A, Oprescu SN, Griffin LB, Heider A, Amalfitano A, Innis JW. 2018. Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease. Hum. Mutat. 39:834–40
    [Google Scholar]
  6. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA et al. 2004. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429:413–17
    [Google Scholar]
  7. Bataillard M, Chatzoglou E, Rumbach L, Sternberg D, Tournade A et al. 2001. Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation. Neurology 56:405–7
    [Google Scholar]
  8. Bayat V, Thiffault I, Jaiswal M, Tetreault M, Donti T et al. 2012. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLOS Biol. 10:e1001288
    [Google Scholar]
  9. Behrens A, Rodschinka G, Nedialkova DD. 2021. High-resolution quantitative profiling of tRNA abundance and modification status in eukaryotes by mim-tRNAseq. Mol. Cell 81:1802–15.e7
    [Google Scholar]
  10. Benoy V, Van Helleputte L, Prior R, d'Ydewalle C, Haeck W et al. 2018. HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease. Brain 141:673–87
    [Google Scholar]
  11. Blanchet S, Cornu D, Hatin I, Grosjean H, Bertin P, Namy O. 2018. Deciphering the reading of the genetic code by near-cognate tRNA. PNAS 115:3018–23
    [Google Scholar]
  12. Blanco S, Dietmann S, Flores JV, Hussain S, Kutter C et al. 2014. Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J. 33:2020–39
    [Google Scholar]
  13. Blaze J, Navickas A, Phillips HL, Heissel S, Plaza-Jennings A et al. 2021. Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior. Nat. Commun. 12:4913
    [Google Scholar]
  14. Bosl MR, Takaku K, Oshima M, Nishimura S, Taketo MM. 1997. Early embryonic lethality caused by targeted disruption of the mouse selenocysteine tRNA gene (Trsp). PNAS 94:5531–34
    [Google Scholar]
  15. Botta E, Theil AF, Raams A, Caligiuri G, Giachetti S et al. 2021. Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy. Hum. Mol. Genet. 30:1711–20
    [Google Scholar]
  16. Breuss MW, Sultan T, James KN, Rosti RO, Scott E et al. 2016. Autosomal-recessive mutations in the tRNA splicing endonuclease subunit TSEN15 cause pontocerebellar hypoplasia and progressive microcephaly. Am. J. Hum. Genet. 99:228–35
    [Google Scholar]
  17. Budde BS, Namavar Y, Barth PG, Poll-The BT, Nurnberg G et al. 2008. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat. Genet. 40:1113–18
    [Google Scholar]
  18. Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS et al. 2012. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4:118ra10
    [Google Scholar]
  19. Carlson BA, Moustafa ME, Sengupta A, Schweizer U, Shrimali R et al. 2007. Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34. J. Biol. Chem. 282:32591–602
    [Google Scholar]
  20. Carlson BA, Yoo MH, Tsuji PA, Gladyshev VN, Hatfield DL. 2009. Mouse models targeting selenocysteine tRNA expression for elucidating the role of selenoproteins in health and development. Molecules 14:3509–27
    [Google Scholar]
  21. Chen Z, Qi M, Shen B, Luo G, Wu Y et al. 2019. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 47:2533–45
    [Google Scholar]
  22. Chujo T, Tomizawa K. 2021. Human transfer RNA modopathies: diseases caused by aberrations in transfer RNA modifications. FEBS J. 288:7096–122
    [Google Scholar]
  23. Crivello M, O'Riordan SL, Woods I, Cannon S, Halang L et al. 2018. Pleiotropic activity of systemically delivered angiogenin in the SOD1G93A mouse model. Neuropharmacology 133:503–11
    [Google Scholar]
  24. Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ et al. 2014. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82:2063–71
    [Google Scholar]
  25. de Vries H, Ruegsegger U, Hubner W, Friedlein A, Langen H, Keller W. 2000. Human pre-mRNA cleavage factor IIm contains homologs of yeast proteins and bridges two other cleavage factors. EMBO J. 19:5895–904
    [Google Scholar]
  26. Diodato D, Melchionda L, Haack TB, Dallabona C, Baruffini E et al. 2014. VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Hum. Mutat 35:983–89
    [Google Scholar]
  27. Dittmar KA, Goodenbour JM, Pan T. 2006. Tissue-specific differences in human transfer RNA expression. PLOS Genet. 2:e221
    [Google Scholar]
  28. Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I et al. 2007. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J. Hum. Genet. 81:857–62
    [Google Scholar]
  29. Ehrlich R, Davyt M, Lopez I, Chalar C, Marin M. 2021. On the track of the missing tRNA genes: a source of non-canonical functions?. Front. Mol. Biosci. 8:643701
    [Google Scholar]
  30. Fett JW, Strydom DJ, Lobb RR, Alderman EM, Bethune JL et al. 1985. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24:5480–86
    [Google Scholar]
  31. Frasquet M, Sevilla T. 2022. Hereditary motor neuropathies. Curr. Opin. Neurol. 35:562–70
    [Google Scholar]
  32. Froelich CA, First EA. 2011. Dominant intermediate Charcot-Marie-Tooth disorder is not due to a catalytic defect in tyrosyl-tRNA synthetase. Biochemistry 50:7132–45
    [Google Scholar]
  33. Galatolo D, Kuo ME, Mullen P, Meyer-Schuman R, Doccini S et al. 2020. Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome. Hum. Mutat. 41:1232–37
    [Google Scholar]
  34. Gingold H, Pilpel Y. 2011. Determinants of translation efficiency and accuracy. Mol. Syst. Biol. 7:481
    [Google Scholar]
  35. Gingold H, Tehler D, Christoffersen NR, Nielsen MM, Asmar F et al. 2014. A dual program for translation regulation in cellular proliferation and differentiation. Cell 158:1281–92
    [Google Scholar]
  36. Girstmair H, Saffert P, Rode S, Czech A, Holland G et al. 2013. Depletion of cognate charged transfer RNA causes translational frameshifting within the expanded CAG stretch in huntingtin. Cell Rep. 3:148–59
    [Google Scholar]
  37. Glock C, Biever A, Tushev G, Nassim-Assir B, Kao A et al. 2021. The translatome of neuronal cell bodies, dendrites, and axons. PNAS 118:e2113929118
    [Google Scholar]
  38. Goodenbour JM, Pan T. 2006. Diversity of tRNA genes in eukaryotes. Nucleic Acids Res. 34:6137–46
    [Google Scholar]
  39. Goto Y, Nonaka I, Horai S. 1990. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–53
    [Google Scholar]
  40. Gotz A, Tyynismaa H, Euro L, Ellonen P, Hyotylainen T et al. 2011. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am. J. Hum. Genet. 88:635–42
    [Google Scholar]
  41. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S et al. 2006. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet. 38:411–13
    [Google Scholar]
  42. Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B et al. 2015. Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on reunion island. Am. J. Hum. Genet. 96:826–31
    [Google Scholar]
  43. Hanada T, Weitzer S, Mair B, Bernreuther C, Wainger BJ et al. 2013. CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature 495:474–80
    [Google Scholar]
  44. Hayne CK, Schmidt CA, Haque MI, Matera AG, Stanley RE. 2020. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage. Nucleic Acids Res. 48:7609–22
    [Google Scholar]
  45. He J, Liu X-X, Ma M-M, Lin J-J, Fu J et al. 2023. Heterozygous seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease. Ann. Neurol. 93:2244–56
    [Google Scholar]
  46. He W, Bai G, Zhou H, Wei N, White NM et al. 2015. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526:710–14
    [Google Scholar]
  47. Hershberg R, Petrov DA. 2008. Selection on codon bias. Annu. Rev. Genet. 42:287–99
    [Google Scholar]
  48. Hines TJ, Lutz C, Murray SA, Burgess RW. 2022a. An integrated approach to studying rare neuromuscular diseases using animal and human cell-based models. Front. Cell Dev. Biol. 9:801819
    [Google Scholar]
  49. Hines TJ, Tadenev ALD, Lone MA, Hatton CL, Bagasrawala I et al. 2022b. Precision mouse models of Yars/dominant intermediate Charcot-Marie-Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1. J. Anat. 241:1169–85
    [Google Scholar]
  50. Holt CE, Martin KC, Schuman EM. 2019. Local translation in neurons: visualization and function. Nat. Struct. Mol. Biol. 26:557–66
    [Google Scholar]
  51. Hou Y-M. 2010. CCA addition to tRNA: implications for tRNA quality control. IUBMB Life 62:251–60
    [Google Scholar]
  52. Hu G-F. 1998. Neomycin inhibits angiogenin-induced angiogenesis. PNAS 95:9791–95
    [Google Scholar]
  53. Hurtig JE, Steiger MA, Nagarajan VK, Li T, Chao TC et al. 2021. Comparative parallel analysis of RNA ends identifies mRNA substrates of a tRNA splicing endonuclease-initiated mRNA decay pathway. PNAS 118:e2020429118
    [Google Scholar]
  54. Ibba M, Soll D. 2000. Aminoacyl-tRNA synthesis. Annu. Rev. Biochem. 69:617–50
    [Google Scholar]
  55. Iben JR, Maraia RJ. 2014. tRNA gene copy number variation in humans. Gene 536:376–84
    [Google Scholar]
  56. Ishimura R, Nagy G, Dotu I, Chuang JH, Ackerman SL. 2016. Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation. eLife 5:e14295
    [Google Scholar]
  57. Ishimura R, Nagy G, Dotu I, Zhou H, Yang XL et al. 2014. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345:455–59
    [Google Scholar]
  58. Ishitani R, Nureki O, Nameki N, Okada N, Nishimura S, Yokoyama S. 2003. Alternative tertiary structure of tRNA for recognition by a posttranscriptional modification enzyme. Cell 113:383–94
    [Google Scholar]
  59. Ivanov P, Emara MM, Villen J, Gygi SP, Anderson P. 2011. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43:613–23
    [Google Scholar]
  60. Jordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K et al. 2006. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat. Genet. 38:197–202
    [Google Scholar]
  61. Kapur M, Ganguly A, Nagy G, Adamson SI, Chuang JH et al. 2020. Expression of the neuronal tRNA n-Tr20 regulates synaptic transmission and seizure susceptibility. Neuron 108:193–208.e9
    [Google Scholar]
  62. Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T et al. 2014. Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell 157:636–50
    [Google Scholar]
  63. Khan MA, Rafiq MA, Noor A, Hussain S, Flores JV et al. 2012. Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am. J. Hum. Genet. 90:856–63
    [Google Scholar]
  64. Kieran D, Sebastia J, Greenway MJ, King MA, Connaughton D et al. 2008. Control of motoneuron survival by angiogenin. J. Neurosci. 28:14056–61
    [Google Scholar]
  65. Kim SH, Suddath FL, Quigley GJ, McPherson A, Sussman JL et al. 1974. Three-dimensional tertiary structure of yeast phenylalanine transfer RNA. Science 185:435–40
    [Google Scholar]
  66. Kirino Y, Suzuki T. 2005. Human mitochondrial diseases associated with tRNA wobble modification deficiency. RNA Biol. 2:41–44
    [Google Scholar]
  67. Kirino Y, Yasukawa T, Ohta S, Akira S, Ishihara K et al. 2004. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. PNAS 101:15070–75
    [Google Scholar]
  68. Kobayashi Y, Momoi MY, Tominaga K, Momoi T, Nihei K et al. 1990. A point mutation in the mitochondrial tRNALeu (UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem. Biophys. Res. Commun. 173:816–22
    [Google Scholar]
  69. Kobayashi Y, Momoi MY, Tominaga K, Shimoizumi H, Nihei K et al. 1991. Respiration-deficient cells are caused by a single point mutation in the mitochondrial tRNA-Leu (UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Am. J. Hum. Genet. 49:590–99
    [Google Scholar]
  70. Kopajtich R, Murayama K, Janecke AR, Haack TB, Breuer M et al. 2016. Biallelic IARS mutations cause growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and infantile hepatopathy. Am. J. Hum. Genet. 99:414–22
    [Google Scholar]
  71. Koppel I, Fainzilber M. 2018. Omics approaches for subcellular translation studies. Mol. Omics 14:380–88
    [Google Scholar]
  72. Kuo ME, Antonellis A. 2020. Ubiquitously expressed proteins and restricted phenotypes: exploring cell-specific sensitivities to impaired tRNA charging. Trends Genet. 36:2105–17
    [Google Scholar]
  73. Kuo ME, Theil AF, Kievit A, Malicdan MC, Introne WJ et al. 2019. Cysteinyl-tRNA synthetase mutations cause a multi-system, recessive disease that includes microcephaly, developmental delay, and brittle hair and nails. Am. J. Hum. Genet. 104:520–29
    [Google Scholar]
  74. Kutter C, Brown GD, Gonçalves Â, Wilson MD, Watt S et al. 2011. Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes. Nat. Genet. 43:948–55
    [Google Scholar]
  75. Labunskyy VM, Hatfield DL, Gladyshev VN. 2014. Selenoproteins: molecular pathways and physiological roles. Physiol. Rev. 94:739–77
    [Google Scholar]
  76. Laguesse S, Creppe C, Nedialkova DD, Prevot PP, Borgs L et al. 2015. A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev. Cell 35:553–67
    [Google Scholar]
  77. Lange C, Storkebaum E, de Almodovar CR, Dewerchin M, Carmeliet P. 2016. Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat. Rev. Neurol. 12:439–54
    [Google Scholar]
  78. Latour P, Thauvin-Robinet C, Baudelet-Mery C, Soichot P, Cusin V et al. 2010. A major determinant for binding and aminoacylation of tRNAAla in cytoplasmic alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 86:77–82
    [Google Scholar]
  79. Laura M, Pipis M, Rossor AM, Reilly MM. 2019. Charcot-Marie-Tooth disease and related disorders: an evolving landscape. Curr. Opin. Neurol. 32:641–50
    [Google Scholar]
  80. Lin SJ, Vona B, Porter HM, Izadi M, Huang K et al. 2022. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Hum. Mutat. 43:1472–89
    [Google Scholar]
  81. Lyons SM, Fay MM, Akiyama Y, Anderson PJ, Ivanov P. 2017. RNA biology of angiogenin: current state and perspectives. RNA Biol. 14:171–78
    [Google Scholar]
  82. Mancuso M, Filosto M, Mootha VK, Rocchi A, Pistolesi S et al. 2004. A novel mitochondrial tRNAPhe mutation causes MERRF syndrome. Neurology 62:2119–21
    [Google Scholar]
  83. Manfredi G, Schon EA, Bonilla E, Moraes CT, Shanske S, DiMauro S. 1996. Identification of a mutation in the mitochondrial tRNACys gene associated with mitochondrial encephalopathy. Hum. Mutat. 7:158–63
    [Google Scholar]
  84. Martinez FJ, Lee JH, Lee JE, Blanco S, Nickerson E et al. 2012. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J. Med. Genet. 49:380–85
    [Google Scholar]
  85. McLaughlin HM, Sakaguchi R, Liu C, Igarashi T, Pehlivan D et al. 2010. Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am. J. Hum. Genet. 87:560–66
    [Google Scholar]
  86. Melone MA, Tessa A, Petrini S, Lus G, Sampaolo S et al. 2004. Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype. Arch Neurol. 61:269–72
    [Google Scholar]
  87. Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS et al. 2018. Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA synthetase, cause a hypomyelinating leukodystrophy. Am. J. Hum. Genet. 102:676–84
    [Google Scholar]
  88. Meyer-Schuman R, Antonellis A. 2017. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Hum. Mol. Genet. 26:R114–27
    [Google Scholar]
  89. Mo Z, Zhao X, Liu H, Hu Q, Chen XQ et al. 2018. Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. Nat. Commun. 9:1007
    [Google Scholar]
  90. Monaghan CE, Adamson SI, Kapur M, Chuang JH, Ackerman SL. 2021. The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia. PNAS 118:e2110730118
    [Google Scholar]
  91. Moraes CT, Ciacci F, Bonilla E, Jansen C, Hirano M et al. 1993. Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot?. J. Clin. Investig. 92:2906–15
    [Google Scholar]
  92. Morelli KH, Griffin LB, Pyne NK, Wallace LM, Fowler AM et al. 2019. Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models. J. Clin. Investig. 129:5568–83
    [Google Scholar]
  93. Morisaki I, Shiraishi H, Fujinami H, Shimizu N, Hikida T et al. 2021. Modeling a human CLP1 mutation in mouse identifies an accumulation of tyrosine pre-tRNA fragments causing pontocerebellar hypoplasia type 10. Biochem. Biophys. Res. Commun. 570:60–66
    [Google Scholar]
  94. Moroianu J, Riordan JF. 1994. Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity. PNAS 91:1677–81
    [Google Scholar]
  95. Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J et al. 2011. Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels. PLOS Genet. 7:e1002399
    [Google Scholar]
  96. Nafisinia M, Riley LG, Gold WA, Bhattacharya K, Broderick CR et al. 2017. Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. PLOS ONE 12:e0178125
    [Google Scholar]
  97. Nakamura M, Nakano S, Goto Y, Ozawa M, Nagahama Y et al. 1995. A novel point mutation in the mitochondrial tRNASer(UCN) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem. Biophys. Res. Commun. 214:86–93
    [Google Scholar]
  98. Nakayama T, Wu J, Galvin-Parton P, Weiss J, Andriola MR et al. 2017. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum. Mutat. 38:1348–54
    [Google Scholar]
  99. Nangle LA, Zhang W, Xie W, Yang XL, Schimmel P. 2007. Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. PNAS 104:11239–44
    [Google Scholar]
  100. Niehues S, Bussmann J, Steffes G, Erdmann I, Kohrer C et al. 2015. Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat. Commun. 6:7520
    [Google Scholar]
  101. Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL et al. 2014. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343:506–11
    [Google Scholar]
  102. Okamoto N, Miya F, Tsunoda T, Kanemura Y, Saitoh S et al. 2022. Four pedigrees with aminoacyl-tRNA synthetase abnormalities. Neurol. Sci. 43:2765–74
    [Google Scholar]
  103. Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC et al. 2017. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum. Mutat. 38:1412–20
    [Google Scholar]
  104. Orellana EA, Siegal E, Gregory RI. 2022. tRNA dysregulation and disease. Nat. Rev. Genet. 23:651–64
    [Google Scholar]
  105. Pan T. 2018. Modifications and functional genomics of human transfer RNA. Cell Res. 28:395–404
    [Google Scholar]
  106. Pareyson D, Marchesi C. 2009. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 8:654–67
    [Google Scholar]
  107. Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. 2004. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3′ end formation. Cell 117:311–21
    [Google Scholar]
  108. Pinkard O, McFarland S, Sweet T, Coller J. 2020. Quantitative tRNA-sequencing uncovers metazoan tissue-specific tRNA regulation. Nat. Commun. 11:4104
    [Google Scholar]
  109. Plotkin JB, Kudla G. 2011. Synonymous but not the same: the causes and consequences of codon bias. Nat. Rev. Genet. 12:32–42
    [Google Scholar]
  110. Rauscher R, Bampi GB, Guevara-Ferrer M, Santos LA, Joshi D et al. 2021. Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity. PNAS 118:e2010612118
    [Google Scholar]
  111. Ravel JM, Dreumont N, Mosca P, Smith DEC, Mendes MI et al. 2021. A bi-allelic loss-of-function SARS1 variant in children with neurodevelopmental delay, deafness, cardiomyopathy, and decompensation during fever. Hum. Mutat. 42:1576–83
    [Google Scholar]
  112. Ravn K, Wibrand F, Hansen FJ, Horn N, Rosenberg T, Schwartz M. 2001. An mtDNA mutation, 14453G→A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur. J. Hum. Genet. 9:805–9
    [Google Scholar]
  113. Richter U, Evans ME, Clark WC, Marttinen P, Shoubridge EA et al. 2018. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat. Commun. 9:3966
    [Google Scholar]
  114. Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M et al. 2010. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia—MLASA syndrome. Am. J. Hum. Genet. 87:52–59
    [Google Scholar]
  115. Robertus JD, Ladner JE, Finch JT, Rhodes D, Brown RS et al. 1974. Structure of yeast phenylalanine tRNA at 3 Å resolution. Nature 250:546–51
    [Google Scholar]
  116. Rossor AM, Polke JM, Houlden H, Reilly MM. 2013. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat. Rev. Neurol. 9:562–71
    [Google Scholar]
  117. Rubio MA, Rinehart JJ, Krett B, Duvezin-Caubet S, Reichert AS et al. 2008. Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import. PNAS 105:9186–91
    [Google Scholar]
  118. Rubio Gomez MA, Ibba M 2020. Aminoacyl-tRNA synthetases. RNA 26:910–36
    [Google Scholar]
  119. Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC et al. 2007. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res. 35:D823–28
    [Google Scholar]
  120. Safka Brozkova D, Deconinck T, Griffin LB, Ferbert A, Haberlova J et al. 2015. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain 138:2161–72
    [Google Scholar]
  121. Sagi-Dain L, Shemer L, Zelnik N, Zoabi Y, Orit S et al. 2018. Whole-exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U. J. Peripher. Nerv. Syst. 23:138–42
    [Google Scholar]
  122. Saikia M, Jobava R, Parisien M, Putnam A, Krokowski D et al. 2014. Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress. Mol. Cell. Biol. 34:2450–63
    [Google Scholar]
  123. Santorelli FM, Siciliano G, Casali C, Basirico MG, Carrozzo R et al. 1997. Mitochondrial tRNACys gene mutation (A5814G): a second family with mitochondrial encephalopathy. Neuromuscul. Disord. 7:156–59
    [Google Scholar]
  124. Sasarman F, Nishimura T, Thiffault I, Shoubridge EA. 2012. A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia. Hum. Mutat. 33:1201–6
    [Google Scholar]
  125. Schaefer M, Pollex T, Hanna K, Tuorto F, Meusburger M et al. 2010. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 24:1590–95
    [Google Scholar]
  126. Schaffer AE, Eggens VR, Caglayan AO, Reuter MS, Scott E et al. 2014. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157:651–63
    [Google Scholar]
  127. Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M et al. 2007. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat. Genet. 39:534–39
    [Google Scholar]
  128. Schmitt BM, Rudolph KL, Karagianni P, Fonseca NA, White RJ et al. 2014. High-resolution mapping of transcriptional dynamics across tissue development reveals a stable mRNA-tRNA interface. Genome Res. 24:1797–807
    [Google Scholar]
  129. Schneider A. 2011. Mitochondrial tRNA import and its consequences for mitochondrial translation. Annu. Rev. Biochem. 80:1033–53
    [Google Scholar]
  130. Schoenmakers E, Carlson B, Agostini M, Moran C, Rajanayagam O et al. 2016. Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis. J. Clin. Investig. 126:992–96
    [Google Scholar]
  131. Schurer H, Schiffer S, Marchfelder A, Morl M. 2001. This is the end: processing, editing and repair at the tRNA 3′-terminus. Biol. Chem. 382:1147–56
    [Google Scholar]
  132. Sebastia J, Kieran D, Breen B, King MA, Netteland DF et al. 2009. Angiogenin protects motoneurons against hypoxic injury. Cell Death Differ. 16:1238–47
    [Google Scholar]
  133. Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW. 2006. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51:715–26
    [Google Scholar]
  134. Sekulovski S, Devant P, Panizza S, Gogakos T, Pitiriciu A et al. 2021. Assembly defects of human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia. Nat. Commun. 12:5610
    [Google Scholar]
  135. Shapiro R, Vallee BL. 1989. Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. Biochemistry 28:7401–8
    [Google Scholar]
  136. Shetty SP, Copeland PR. 2015. Selenocysteine incorporation: a trump card in the game of mRNA decay. Biochimie 114:97–101
    [Google Scholar]
  137. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. 1990. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61:931–37
    [Google Scholar]
  138. Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S. 1992. A new mtDNA mutation in the tRNALys gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51:1213–17
    [Google Scholar]
  139. Simon M, Richard EM, Wang X, Shahzad M, Huang VH et al. 2015. Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLOS Genet. 11:e1005097
    [Google Scholar]
  140. Simons C, Griffin LB, Helman G, Golas G, Pizzino A et al. 2015. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am. J. Hum. Genet. 96:675–81
    [Google Scholar]
  141. Sleigh JN, Dawes JM, West SJ, Wei N, Spaulding EL et al. 2017. Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. PNAS 114:E3324–33
    [Google Scholar]
  142. Spaulding EL, Burgess RW. 2017. Accumulating evidence for axonal translation in neuronal homeostasis. Front. Neurosci. 11:312
    [Google Scholar]
  143. Spaulding EL, Hines TJ, Bais P, Tadenev ALD, Schneider R et al. 2021. The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science 373:1156–61
    [Google Scholar]
  144. Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D et al. 2012. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain 135:1387–94
    [Google Scholar]
  145. Storkebaum E. 2016. Peripheral neuropathy via mutant tRNA synthetases: inhibition of protein translation provides a possible explanation. Bioessays 38:818–29
    [Google Scholar]
  146. Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S et al. 2005. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat. Neurosci. 8:85–92
    [Google Scholar]
  147. Storkebaum E, Leitao-Goncalves R, Godenschwege T, Nangle L, Mejia M et al. 2009. Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy. PNAS 106:11782–87
    [Google Scholar]
  148. Su Z, Wilson B, Kumar P, Dutta A. 2020. Noncanonical roles of tRNAs: tRNA fragments and beyond. Annu. Rev. Genet. 54:47–69
    [Google Scholar]
  149. Subramanian V, Crabtree B, Acharya KR. 2008. Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons. Hum. Mol. Genet. 17:130–49
    [Google Scholar]
  150. Sun L, Wei N, Kuhle B, Blocquel D, Novick S et al. 2021. CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS. PNAS 118:e2012898118
    [Google Scholar]
  151. Sun M, Zhang J. 2022. Preferred synonymous codons are translated more accurately: proteomic evidence, among-species variation, and mechanistic basis. Sci. Adv. 8:eabl9812
    [Google Scholar]
  152. Suzuki T, Yashiro Y, Kikuchi I, Ishigami Y, Saito H et al. 2020. Complete chemical structures of human mitochondrial tRNAs. Nat. Commun. 11:4269
    [Google Scholar]
  153. Taylor JP, Brown RH Jr., Cleveland DW. 2016. Decoding ALS: from genes to mechanism. Nature 539:197–206
    [Google Scholar]
  154. Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J et al. 2014. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 312:68–77
    [Google Scholar]
  155. Taylor RW, Schaefer AM, McDonnell MT, Petty RK, Thomas AM et al. 2004. Catastrophic presentation of mitochondrial disease due to a mutation in the tRNAHis gene. Neurology 62:1420–23
    [Google Scholar]
  156. Terrey M, Adamson SI, Gibson AL, Deng T, Ishimura R et al. 2020. GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis. eLife 9:e62731
    [Google Scholar]
  157. Theil AF, Botta E, Raams A, Smith DEC, Mendes MI et al. 2019. Bi-allelic TARS mutations are associated with brittle hair phenotype. Am. J. Hum. Genet. 105:434–40
    [Google Scholar]
  158. Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN et al. 2017. Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. Am. J. Med. Genet. A 173:2505–10
    [Google Scholar]
  159. Thiyagarajan N, Ferguson R, Subramanian V, Acharya KR. 2012. Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons. Nat. Commun. 3:1121
    [Google Scholar]
  160. Thomas NK, Poodari VC, Jain M, Olsen HE, Akeson M, Abu-Shumays RL. 2021. Direct nanopore sequencing of individual full length tRNA strands. ACS Nano 15:16642–53
    [Google Scholar]
  161. Thornlow BP, Hough J, Roger JM, Gong H, Lowe TM, Corbett-Detig RB. 2018. Transfer RNA genes experience exceptionally elevated mutation rates. PNAS 115:8996–9001
    [Google Scholar]
  162. Tolkunova E, Park H, Xia J, King MP, Davidson E. 2000. The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript. J. Biol. Chem. 275:35063–69
    [Google Scholar]
  163. Tsai PC, Soong BW, Mademan I, Huang YH, Liu CR et al. 2017. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. Brain 140:1252–66
    [Google Scholar]
  164. Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S et al. 2012. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat. Struct. Mol. Biol. 19:900–5
    [Google Scholar]
  165. Turner RJ, Lovato M, Schimmel P. 2000. One of two genes encoding glycyl-tRNA synthetase in Saccharomyces cerevisiae provides mitochondrial and cytoplasmic functions. J. Biol. Chem. 275:27681–88
    [Google Scholar]
  166. Turvey AK, Horvath GA, Cavalcanti ARO. 2022. Aminoacyl-tRNA synthetases in human health and disease. Front. Physiol. 13:1029218
    [Google Scholar]
  167. van Dijk T, Baas F, Barth PG, Poll-The BT. 2018. What's new in pontocerebellar hypoplasia? An update on genes and subtypes. Orphanet J. Rare Dis. 13:92
    [Google Scholar]
  168. van Es MA, Schelhaas HJ, van Vught PW, Ticozzi N, Andersen PM et al. 2011. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann. Neurol. 70:964–73
    [Google Scholar]
  169. van Meel E, Wegner DJ, Cliften P, Willing MC, White FV et al. 2013. Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med. Genet. 14:106
    [Google Scholar]
  170. Vanlander AV, Menten B, Smet J, De Meirleir L, Sante T et al. 2015. Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). Hum. Mutat. 36:222–31
    [Google Scholar]
  171. Wang L, Li Z, Sievert D, Smith DEC, Mendes MI et al. 2020. Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. Nat. Commun. 11:4038
    [Google Scholar]
  172. Wang X, Matuszek Z, Huang Y, Parisien M, Dai Q et al. 2018. Queuosine modification protects cognate tRNAs against ribonuclease cleavage. RNA 24:1305–13
    [Google Scholar]
  173. Ward CL, Kopito RR. 1994. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J. Biol. Chem. 269:25710–18
    [Google Scholar]
  174. Webb BD, Wheeler PG, Hagen JJ, Cohen N, Linderman MD et al. 2015. Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. Hum. Mutat. 36:587–92
    [Google Scholar]
  175. Wei N, Zhang Q, Yang XL. 2019. Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases. J. Biol. Chem. 294:5321–39
    [Google Scholar]
  176. Weitzer S, Martinez J. 2007. The human RNA kinase hClp1 is active on 3′ transfer RNA exons and short interfering RNAs. Nature 447:222–26
    [Google Scholar]
  177. Weterman MAJ, Kuo M, Kenter SB, Gordillo S, Karjosukarso DW et al. 2018. Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities. Hum. Mol. Genet. 27:4036–50
    [Google Scholar]
  178. Williams KB, Brigatti KW, Puffenberger EG, Gonzaga-Jauregui C, Griffin LB et al. 2019. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease. Hum. Mol. Genet. 28:525–38
    [Google Scholar]
  179. Wong LJ, Yim D, Bai RK, Kwon H, Vacek MM et al. 2006. A novel mutation in the mitochondrial tRNASer(AGY) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiency. J. Med. Genet. 43:e46
    [Google Scholar]
  180. Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R et al. 2017. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum. Mutat. 38:1786–95
    [Google Scholar]
  181. Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ et al. 2007. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann. Neurol. 62:609–17
    [Google Scholar]
  182. Xiao S, Scott F, Fierke CA, Engelke DR. 2002. Eukaryotic ribonuclease P: a plurality of ribonucleoprotein enzymes. Annu. Rev. Biochem. 71:165–89
    [Google Scholar]
  183. Xu ZP, Tsuji T, Riordan JF, Hu GF. 2002. The nuclear function of angiogenin in endothelial cells is related to rRNA production. Biochem. Biophys. Res. Commun. 294:287–92
    [Google Scholar]
  184. Yamasaki S, Ivanov P, Hu GF, Anderson P. 2009. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J. Cell Biol. 185:35–42
    [Google Scholar]
  185. Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K. 2000. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAsLeu(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J. Biol. Chem. 275:4251–57
    [Google Scholar]
  186. Yoneda M, Tanno Y, Horai S, Ozawa T, Miyatake T, Tsuji S. 1990. A common mitochondrial DNA mutation in the t-RNA(Lys) of patients with myoclonus epilepsy associated with ragged-red fibers. Biochem. Int. 21:789–96
    [Google Scholar]
  187. Yu W, Goncalves KA, Li S, Kishikawa H, Sun G et al. 2017. Plexin-B2 Mediates physiologic and pathologic functions of angiogenin. Cell 171:849–64.e25
    [Google Scholar]
  188. Zeviani M, Muntoni F, Savarese N, Serra G, Tiranti V et al. 1993. A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNALys gene. Eur. J. Hum. Genet. 1:80–87
    [Google Scholar]
  189. Zhang X, Ling J, Barcia G, Jing L, Wu J et al. 2014. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am. J. Hum. Genet. 94:547–58
    [Google Scholar]
  190. Zheng G, Qin Y, Clark WC, Dai Q, Yi C et al. 2015. Efficient and quantitative high-throughput tRNA sequencing. Nat. Methods 12:835–37
    [Google Scholar]
  191. Zuko A, Mallik M, Thompson R, Spaulding EL, Wienand AR et al. 2021. tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science 373:1161–66
    [Google Scholar]
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