2016/04/30 by Metodi D. Metodiev, Metodi D. Metodiev, Kyle Thompson +22 · 25 citations
Biochemistry, Genetics and Molecular Biology · #Genetics and Neurodevelopmental Disorders #Genomics and Rare Diseases #Mitochondrial Function and Pathology
paper · pdf · doi:10.1016/j.ajhg.2016.03.010
Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5′ ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m1R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants—compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2—was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m1R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function. Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5′ ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m1R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants—compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2—was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m1R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function. Mitochondrial respiratory chain deficiencies lead to insufficient ATP production from oxidative phosphorylation (OXPHOS), resulting in a wide range of clinical presentations broadly recognized as “mitochondrial disorders.” Mitochondrial diseases are genetically diverse, owing to the necessary expression, co-ordination, and activity of factors encoded by both the mitochondrial and nuclear genomes for proper mitochondrial function. The 16.6 kb human mitochondrial DNA (mtDNA) encodes only 22 tRNAs, 2 rRNAs, and 13 polypeptides that are essential components of four of the five OXPHOS complexes.1Anderson S. Bankier A.T. Barrell B.G. de Bruijn M.H. Coulson A.R. Drouin J. Eperon I.C. Nierlich D.P. Roe B.A. Sanger F. et al.Sequence and organization of the human mitochondrial genome.Nature. 1981; 290: 457-465Crossref PubMed Scopus (7612) Google Scholar The remaining subunits of the respiratory complexes and all of the factors involved in mtDNA expression and maintenance are encoded by the nuclear genome, synthesized in the cytosol, and imported into mitochondria. Thus, there are a large number of potential genetic causes of mitochondrial disease, which has often complicated attempts to identify the correct genetic diagnosis. The advent of next generation sequencing has greatly expanded the list of known gene mutations associated with mitochondrial disease,2Taylor R.W. Pyle A. Griffin H. Blakely E.L. Duff J. He L. Smertenko T. Alston C.L. Neeve V.C. Best A. et al.Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.JAMA. 2014; 312: 68-77Crossref PubMed Scopus (252) Google Scholar including several genes involved in mitochondrial (mt)-tRNA processing and maturation.3Powell C.A. Nicholls T.J. Minczuk M. Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease.Front. Genet. 2015; 6: 79Crossref PubMed Scopus (53) Google Scholar, 4Lightowlers R.N. Taylor R.W. Turnbull D.M. Mutations causing mitochondrial disease: What is new and what challenges remain?.Science. 2015; 349: 1494-1499Crossref PubMed Scopus (198) Google Scholar In mammalian mitochondria, all mt-tRNAs required for mitochondrial protein synthesis are encoded by the mitochondrial genome. Transcription of mtDNA produces long polycistronic transcripts that require further processing. Most mitochondrial open reading frames are separated by at least one mt-tRNA gene, with the structure of mt-tRNAs acting as “punctuation” marks in the transcript5Ojala D. Montoya J. Attardi G. tRNA punctuation model of RNA processing in human mitochondria.Nature. 1981; 290: 470-474Crossref PubMed Scopus (1851) Google Scholar prior to mt-tRNAs being excised at the 5′ end by the RNase P complex and at the 3′ end by the RNase Z enzyme. The mitochondrial RNase P in animals is composed of three proteins, MRPP1, MRPP2, and MRPP36Holzmann J. Frank P. Löffler E. Bennett K.L. Gerner C. Rossmanith W. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme.Cell. 2008; 135: 462-474Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar (encoded by TRMT10C [MIM: 615423], HSD17B10 [MIM: 300256], and KIAA0391 [MIM: 609947], respectively), whereas RNase Z is encoded by a single gene, ELAC2 (MIM: 605367).7Sanchez M.I.G.L. Mercer T.R. Davies S.M.K. Shearwood A.-M.J. Nygård K.K.A. Richman T.R. Mattick J.S. Rackham O. Filipovska A. RNA processing in human mitochondria.Cell Cycle. 2011; 10: 2904-2916Crossref PubMed Scopus (177) Google Scholar, 8Brzezniak L.K. Bijata M. Szczesny R.J. Stepien P.P. Involvement of human ELAC2 gene product in 3′ end processing of mitochondrial tRNAs.RNA Biol. 2011; 8: 616-626Crossref PubMed Scopus (129) Google Scholar, 9Takaku H. Minagawa A. Takagi M. Nashimoto M. A candidate prostate cancer susceptibility gene encodes tRNA 3′ processing endoribonuclease.Nucleic Acids Res. 2003; 31: 2272-2278Crossref PubMed Scopus (149) Google Scholar, 10Rossmanith W. Localization of human RNase Z isoforms: dual nuclear/mitochondrial targeting of the ELAC2 gene product by alternative translation initiation.PLoS ONE. 2011; 6: e19152Crossref PubMed Scopus (58) Google Scholar In addition to cleavage from the polycistronic transcripts, mt-tRNAs undergo many further modifications, with at least 30 different modified residues reported.3Powell C.A. Nicholls T.J. Minczuk M. Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease.Front. Genet. 2015; 6: 79Crossref PubMed Scopus (53) Google Scholar, 11Suzuki T. Suzuki T. A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAs.Nucleic Acids Res. 2014; 42: 7346-7357Crossref PubMed Scopus (201) Google Scholar One crucial modification is m1R9 methylation, which is probably important for the correct folding of most mt-tRNAs. In the case of mt-tRNALys, the unmodified in vitro transcript folds into an extended bulged hairpin,12Helm M. Brulé H. Degoul F. Cepanec C. Leroux J.P. Giegé R. Florentz C. The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA.Nucleic Acids Res. 1998; 26: 1636-1643Crossref PubMed Scopus (184) Google Scholar but with the sole modification of N1 methylation of adenosine 9 (m1A9), the tRNA adopts the classic cloverleaf structure.13Voigts-Hoffmann F. Hengesbach M. Kobitski A.Y. van Aerschot A. Herdewijn P. Nienhaus G.U. Helm M. A methyl group controls conformational equilibrium in human mitochondrial tRNALys.J. Am. Chem. Soc. 2007; 129: 13382-13383Crossref PubMed Scopus (68) Google Scholar It has been demonstrated that MRPP1 and MRPP2 can form a stable sub-complex that is active as a methyltransferase and is uniquely able to methylate both adenosine and guanine nucleotides at position 9.7Sanchez M.I.G.L. Mercer T.R. Davies S.M.K. Shearwood A.-M.J. Nygård K.K.A. Richman T.R. Mattick J.S. Rackham O. Filipovska A. RNA processing in human mitochondria.Cell Cycle. 2011; 10: 2904-2916Crossref PubMed Scopus (177) Google Scholar, 14Vilardo E. Nachbagauer C. Buzet A. Taschner A. Holzmann J. Rossmanith W. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase--extensive moonlighting in mitochondrial tRNA biogenesis.Nucleic Acids Res. 2012; 40: 11583-11593Crossref PubMed Scopus (150) Google Scholar 19 of the 22 mt-tRNAs contain either A or G at position 9 and it is likely that all of these are subject to m1R9 methylation.7Sanchez M.I.G.L. Mercer T.R. Davies S.M.K. Shearwood A.-M.J. Nygård K.K.A. Richman T.R. Mattick J.S. Rackham O. Filipovska A. RNA processing in human mitochondria.Cell Cycle. 2011; 10: 2904-2916Crossref PubMed Scopus (177) Google Scholar, 11Suzuki T. Suzuki T. A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAs.Nucleic Acids Res. 2014; 42: 7346-7357Crossref PubMed Scopus (201) Google Scholar, 14Vilardo E. Nachbagauer C. Buzet A. Taschner A. Holzmann J. Rossmanith W. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase--extensive moonlighting in mitochondrial tRNA biogenesis.Nucleic Acids Res. 2012; 40: 11583-11593Crossref PubMed Scopus (150) Google Scholar We studied two children with suspected mitochondrial disease from unrelated families. Subject 1 (male) was the second child of healthy, non-consanguineous, white British parents, with a healthy older sister. He was born at term by a normal vaginal delivery after a normal pregnancy with a birth weight of 3.7 kg. He did not require resuscitation but was noted to be hypotonic and weak soon after birth. He fed poorly and gained weight slowly, partly due to gastro-esophageal reflux. Neonatal screening revealed significant hearing impairment subsequently confirmed to be sensorineural deafness. He was also found to have a raised plasma alanine transaminase of 439 U/L (normal range 4–45 U/L). Blood lactate levels ranged from 5 to 10 mmol/L (normal range 0.7–2.1 mmol/L) and his CSF lactate level was also elevated at 4.8 mmol/L. Ophthalmological examination, echocardiography, and an MRI were all normal, though the latter was of poor quality. There was a clinical suspicion of craniosynostosis and a lateral skull X-ray appeared to show fused sutures but no further investigations were undertaken. Ultrasound of the kidneys was normal. Blood spot acylcarnitine analysis and plasma biotinidase were normal, plasma amino acid analysis was normal with the exception of a raised alanine concentration, and urine organic acid analysis was normal apart from a raised lactate concentration. He deteriorated rapidly, requiring tube feeding, and at the age of 4 months suffered rhinovirus bronchiolitis requiring ventilatory support with CPAP. It proved impossible to wean him off ventilatory support and died at months of age after of Subject 2 was the second child of unrelated of with a healthy older was born at term by after a normal kg. poor and feeding were from in the and normal range mmol/L) with a lactate to normal range was at 1 gained weight poorly and feeding was at demonstrated and revealed elevated CSF lactate also impaired normal range normal range normal range MRI was at 2 months of age and was of poor but of were at 4 deafness. potential was not died at 5 months of age from respiratory for and was for both in with the of and by in and analysis of identified mitochondrial defects both complex and in both whereas complex activity was normal in subject 1 but decreased in subject both of complex activity analysis of from subject 1 revealed of mitochondrial and a of and in with TRMT10C in at and chain complex are as complex for complex and for complexes and at hypotonia, sensorineural elevated and CSF lactate chain complex are as 4 at 5 elevated and CSF lactate chain complex are as complex for complex and for complexes and chain complex are as protein in a new of DNA from both mtDNA and and mtDNA number was to be normal in case not sequencing and R.W. Pyle A. Griffin H. Blakely E.L. Duff J. He L. Smertenko T. Alston C.L. Neeve V.C. Best A. et al.Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.JAMA. 2014; 312: 68-77Crossref PubMed Scopus (252) Google Scholar, A. P. P. C. F. et in which encodes a RNA into and causes J. Genet. 2012; Full Text Full Text PDF PubMed Scopus (68) Google Scholar identified variants in TRMT10C (MIM: also known as MRPP1 and heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) variants were identified in subject whereas subject 2 was homozygous for the c.542G>T (p.Arg181Leu) also identified in subject Sanger sequencing was to the variants and that these with disease in Both identified TRMT10C variants are to in amino acid affecting residues and are the c.542G>T (p.Arg181Leu) variant is the and whereas the c.814A>G (p.Thr272Ala) TRMT10C variant is and In and that the of the are but that the of the to the from at a crucial that only an can In of the TRMT10C variants and of MRPP1 protein structure and not be to potential as a of the the functional of the identified TRMT10C and mitochondrial protein synthesis were in from both affected individuals and that the levels of MRPP1 were decreased in the subject that the variants affect the stability of the protein the levels of MRPP2 and MRPP3, the two subunits of RNase were in fibroblasts from affected individuals The of MRPP1 protein level with decreased levels of subunits of complex and complex in with the multiple respiratory chain defects in We to determine the the and stability of the respiratory chain H. P. C. C. J. is a dual mitochondrial protein required for both methylation of and of Genet. 2014; 10: PubMed Scopus Google Scholar and show a of complex and complex with a in complex levels The levels of was due to impaired mitochondrial protein synthesis in subject fibroblasts as demonstrated by of and MRPP1 is known to be an essential of the mitochondrial RNase J. Frank P. Löffler E. Bennett K.L. Gerner C. Rossmanith W. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme.Cell. 2008; 135: 462-474Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar which is for 5′ cleavage of mt-tRNAs from the polycistronic mitochondrial transcripts, we fibroblasts from affected individuals of impaired mitochondrial RNA processing. an increase in RNA precursor detected with either an or the levels of the were not increase in precursors of or were the levels of appeared to be decreased in subject 2 of mt-tRNAs at the 3′ end is by M.I.G.L. Mercer T.R. Davies S.M.K. Shearwood A.-M.J. Nygård K.K.A. Richman T.R. Mattick J.S. Rackham O. Filipovska A. RNA processing in human mitochondria.Cell Cycle. 2011; 10: 2904-2916Crossref PubMed Scopus (177) Google Scholar, 8Brzezniak L.K. Bijata M. Szczesny R.J. Stepien P.P. Involvement of human ELAC2 gene product in 3′ end processing of mitochondrial tRNAs.RNA Biol. 2011; 8: 616-626Crossref PubMed Scopus (129) Google Scholar, 10Rossmanith W. Localization of human RNase Z isoforms: dual nuclear/mitochondrial targeting of the ELAC2 gene product by alternative translation initiation.PLoS ONE. 2011; 6: e19152Crossref PubMed Scopus (58) Google Scholar both functional of it be that the mt-tRNAs be at the 3′ but not at the 5′ resulting in with an mt-tRNA at the 3′ The of the for was not to and these transcripts, were to the levels of mt-tRNAs the levels of mt-tRNAs were not in the affected individuals to that the mitochondrial translation was not due to of mt-tRNAs. and appeared to have levels in subject fibroblasts to further precursor we analysis of mitochondrial RNA from and affected of and mt-tRNA gene expression in and RNA revealed no significant in encoded and mt-tRNA levels the we the changes in the of the mitochondrial we found an increase in the that gene RNA processing is required to mitochondrial from the precursor transcripts these an impairment of mt-tRNA processing without or mt-tRNA It is that the cleavage of mt-tRNAs by P is in harboring but that the mt-tRNAs that are are mt-tRNA levels to wild-type tRNAs undergo modification at to their correct T. Suzuki T. A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAs.Nucleic Acids Res. 2014; 42: 7346-7357Crossref PubMed Scopus (201) Google Scholar, T. A. Suzuki T. mitochondrial and Genet. 2011; PubMed Scopus Google Scholar The mt-tRNAs are not and cleavage from the polycistronic mt-RNA transcripts is one in their In addition to their in RNase P activity, MRPP1 and MRPP2 as an m1R9 E. Nachbagauer C. Buzet A. Taschner A. Holzmann J. Rossmanith W. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase--extensive moonlighting in mitochondrial tRNA biogenesis.Nucleic Acids Res. 2012; 40: 11583-11593Crossref PubMed Scopus (150) Google Scholar of either G or A at position 9 is vital for the correct structure and of M. Brulé H. Degoul F. Cepanec C. Leroux J.P. Giegé R. Florentz C. The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA.Nucleic Acids Res. 1998; 26: 1636-1643Crossref PubMed Scopus (184) Google Scholar, F. Hengesbach M. Kobitski A.Y. van Aerschot A. Herdewijn P. Nienhaus G.U. Helm M. A methyl group controls conformational equilibrium in human mitochondrial tRNALys.J. Am. Chem. Soc. 2007; 129: 13382-13383Crossref PubMed Scopus (68) Google Scholar, M. T. at position 9 with is crucial for structure and of mitochondrial tRNAs the Acids Res. PubMed Scopus Google Scholar Thus, we to the of the TRMT10C variants m1R9 methyltransferase activity in subject we two analysis of mt-tRNAs which the of a is by the presence of m1R9 C.A. R. A.R. J. C. C. Alston C.L. Griffin H. et mutations cause a in post-transcriptional modification of mitochondrial tRNA associated with multiple J. Genet. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar and methylation at position 9 has been to increase the sequencing at M.I.G.L. Mercer T.R. Davies S.M.K. Shearwood A.-M.J. Nygård K.K.A. Richman T.R. Mattick J.S. Rackham O. Filipovska A. RNA processing in human mitochondria.Cell Cycle. 2011; 10: 2904-2916Crossref PubMed Scopus (177) Google Scholar analysis of revealed no and affected individuals there was no in the sequencing subject and that the m1R9 methyltransferase activity is not affected by the and MRPP1 We have demonstrated that tRNA 5′ processing is affected in fibroblasts from affected individuals with MRPP1, which is with of the of MRPP1 as a of P. to that the mitochondrial OXPHOS is a of the TRMT10C lentiviral rescue were to the respiratory in from affected individuals were with a lentiviral a of the wild-type TRMT10C gene encoding The expression of MRPP1 protein level to a of mitochondrial translation and and normal levels of respiratory chain complexes the level of mt-RNA elevated in subject after lentiviral transduction with wild-type TRMT10C the pathogenicity of the c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) TRMT10C these variants as of mitochondrial disease associated with multiple respiratory chain has subsequently been to both in after the identification and of TRMT10C In the harboring heterozygous both TRMT10C variants were identified in a pregnancy after to In 2 the was heterozygous for the c.542G>T (p.Arg181Leu) TRMT10C variant and mitochondrial respiratory chain were normal in the not of an clinical we noted that both affected individuals decreased MRPP1 protein levels in the levels in subject 1 levels subject 2 that the MRPP1 protein is stable the levels of MRPP1, from subject 2 a impairment of mitochondrial protein synthesis resulting in levels of respiratory chain complexes and the protein is stable but active the The impairment of mt-RNA processing in fibroblasts from the affected individuals was not as as we with levels of and mt-tRNAs these with of mutations in involved with RNA that mutations in R. P. T. J. Nicholls T.J. E. A. et mutations cause a mitochondrial RNA processing associated with J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar and A. C. H. S. J. or of 10 cause of MRPP1 and impaired processing of mitochondrial Genet. 2014; PubMed Scopus Google Scholar have both been to lead to an of mt-RNA precursors without the levels of and mt-tRNAs. it has been that of MRPP2 levels to a in levels of A. C. H. S. J. or of 10 cause of MRPP1 and impaired processing of mitochondrial Genet. 2014; PubMed Scopus Google Scholar, M.I.G.L. Shearwood A.-M.J. T. Davies S.M.K. Rackham O. Filipovska A. of mitochondrial gene 2015; PubMed Scopus Google Scholar that the increase in RNA precursors we was to in with HSD17B10 variants (MIM: A. C. H. S. J. or of 10 cause of MRPP1 and impaired processing of mitochondrial Genet. 2014; PubMed Scopus Google Scholar it is that decreased MRPP1 protein levels are important for RNA processing MRPP2 levels were not to be in either of the we did not of m1R9 methyltransferase activity in fibroblasts from either affected that the in mitochondrial protein synthesis is due to a in the of mt-RNA processing mt-tRNA The m1R9 methyltransferase activity is by a stable protein complex of MRPP1 and E. Nachbagauer C. Buzet A. Taschner A. Holzmann J. Rossmanith W. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase--extensive moonlighting in mitochondrial tRNA biogenesis.Nucleic Acids Res. 2012; 40: 11583-11593Crossref PubMed Scopus (150) Google Scholar whereas the RNA processing J. Frank P. Löffler E. Bennett K.L. Gerner C. Rossmanith W. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme.Cell. 2008; 135: 462-474Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar which the active of the activity of RNase L. S. of the of human mitochondrial RNase Acids Res. 2015; PubMed Scopus Google Scholar, F. W. of the human mitochondrial RNase P protein 2015; PubMed Scopus Google Scholar one is to that the and variants the MRPP1 and without affecting the complex with MRPP2, of defects in mt-tRNA processing or modification to disease has expanded in including the variants in HSD17B10 A. C. H. S. J. or of 10 cause of MRPP1 and impaired processing of mitochondrial Genet. 2014; PubMed Scopus Google Scholar and R. P. T. J. Nicholls T.J. E. A. et mutations cause a mitochondrial RNA processing associated with J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar as as mutations in mt-tRNA including E. A. in 1 causes mitochondrial and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar (MIM: Pyle A. S. E. F. C. A. He L. Blakely E.L. et modification of mitochondrial and tRNAs from mutations in and Genet. 2014; 10: PubMed Scopus Google Scholar A. A. O. A. M. O. H. R. et due to mutations in the J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar (MIM: H. T. D. A. et in cause with and 2014; PubMed Scopus Google Scholar (MIM: C.A. R. A.R. J. C. C. Alston C.L. Griffin H. et mutations cause a in post-transcriptional modification of mitochondrial tRNA associated with multiple J. Genet. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar (MIM: E. C. F. L. Blakely E.L. E. C. S. S. et mutations are associated with and lactic and cause respiratory chain in and PubMed Scopus Google Scholar, D. E. F. L. C. R. T. et of the cause and lactic J. Genet. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar (MIM: and R. Nicholls T.J. J. P. H. A. D. R. Taylor R.W. et in cause a mitochondrial translation associated with lactic acidosis, and J. Genet. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar (MIM: Mutations in TRMT10C can be to list as we show that the of wild-type MRPP1 into fibroblasts from affected individuals is to rescue their mitochondrial these TRMT10C variants as in mitochondrial disease associated with impaired mitochondrial was by a and for and Mitochondrial of and and and The and is by a for is a in and a who support from the Mitochondrial the for at and the of is by a from is a and and is by from the and an for A.R. is by the and RNA and sequencing were at the for The in have been in at and in at and for c.542G>T and with Mutations in TRMT10C in Mitochondrial RNA and et of of PDF