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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Recessive Mutations in <italic>TRMT10C</italic> Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies</title><author><name sortKey="Metodiev, Metodi D" sort="Metodiev, Metodi D" uniqKey="Metodiev M" first="Metodi D." last="Metodiev">Metodi D. Metodiev</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Thompson, Kyle" sort="Thompson, Kyle" uniqKey="Thompson K" first="Kyle" last="Thompson">Kyle Thompson</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Alston, Charlotte L" sort="Alston, Charlotte L" uniqKey="Alston C" first="Charlotte L." last="Alston">Charlotte L. Alston</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Morris, Andrew A M" sort="Morris, Andrew A M" uniqKey="Morris A" first="Andrew A. M." last="Morris">Andrew A. M. Morris</name><affiliation><nlm:aff id="aff3">Institute of Human Development, University of Manchester, Manchester M13 9WL, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK</nlm:aff></affiliation></author><author><name sortKey="He, Langping" sort="He, Langping" uniqKey="He L" first="Langping" last="He">Langping He</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Assouline, Zarah" sort="Assouline, Zarah" uniqKey="Assouline Z" first="Zarah" last="Assouline">Zarah Assouline</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Rio, Marlene" sort="Rio, Marlene" uniqKey="Rio M" first="Marlène" last="Rio">Marlène Rio</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bahi Buisson, Nadia" sort="Bahi Buisson, Nadia" uniqKey="Bahi Buisson N" first="Nadia" last="Bahi-Buisson">Nadia Bahi-Buisson</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pyle, Angela" sort="Pyle, Angela" uniqKey="Pyle A" first="Angela" last="Pyle">Angela Pyle</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Griffin, Helen" sort="Griffin, Helen" uniqKey="Griffin H" first="Helen" last="Griffin">Helen Griffin</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Siira, Stefan" sort="Siira, Stefan" uniqKey="Siira S" first="Stefan" last="Siira">Stefan Siira</name><affiliation><nlm:aff id="aff7">Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia</nlm:aff></affiliation></author><author><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name><affiliation><nlm:aff id="aff7">Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia</nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK</nlm:aff></affiliation></author><author><name sortKey="Mcfarland, Robert" sort="Mcfarland, Robert" uniqKey="Mcfarland R" first="Robert" last="Mcfarland">Robert Mcfarland</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnès" last="Rötig">Agnès Rötig</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Taylor, Robert W" sort="Taylor, Robert W" uniqKey="Taylor R" first="Robert W." last="Taylor">Robert W. Taylor</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27132592</idno><idno type="pmc">4863561</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863561</idno><idno type="RBID">PMC:4863561</idno><idno type="doi">10.1016/j.ajhg.2016.03.010</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">001217</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001217</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Recessive Mutations in <italic>TRMT10C</italic> Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies</title><author><name sortKey="Metodiev, Metodi D" sort="Metodiev, Metodi D" uniqKey="Metodiev M" first="Metodi D." last="Metodiev">Metodi D. Metodiev</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Thompson, Kyle" sort="Thompson, Kyle" uniqKey="Thompson K" first="Kyle" last="Thompson">Kyle Thompson</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Alston, Charlotte L" sort="Alston, Charlotte L" uniqKey="Alston C" first="Charlotte L." last="Alston">Charlotte L. Alston</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Morris, Andrew A M" sort="Morris, Andrew A M" uniqKey="Morris A" first="Andrew A. M." last="Morris">Andrew A. M. Morris</name><affiliation><nlm:aff id="aff3">Institute of Human Development, University of Manchester, Manchester M13 9WL, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK</nlm:aff></affiliation></author><author><name sortKey="He, Langping" sort="He, Langping" uniqKey="He L" first="Langping" last="He">Langping He</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Assouline, Zarah" sort="Assouline, Zarah" uniqKey="Assouline Z" first="Zarah" last="Assouline">Zarah Assouline</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Rio, Marlene" sort="Rio, Marlene" uniqKey="Rio M" first="Marlène" last="Rio">Marlène Rio</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bahi Buisson, Nadia" sort="Bahi Buisson, Nadia" uniqKey="Bahi Buisson N" first="Nadia" last="Bahi-Buisson">Nadia Bahi-Buisson</name><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pyle, Angela" sort="Pyle, Angela" uniqKey="Pyle A" first="Angela" last="Pyle">Angela Pyle</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Griffin, Helen" sort="Griffin, Helen" uniqKey="Griffin H" first="Helen" last="Griffin">Helen Griffin</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Siira, Stefan" sort="Siira, Stefan" uniqKey="Siira S" first="Stefan" last="Siira">Stefan Siira</name><affiliation><nlm:aff id="aff7">Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia</nlm:aff></affiliation></author><author><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name><affiliation><nlm:aff id="aff7">Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia</nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation><nlm:aff id="aff6">Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK</nlm:aff></affiliation></author><author><name sortKey="Mcfarland, Robert" sort="Mcfarland, Robert" uniqKey="Mcfarland R" first="Robert" last="Mcfarland">Robert Mcfarland</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author><author><name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnès" last="Rötig">Agnès Rötig</name><affiliation><nlm:aff id="aff1">INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Taylor, Robert W" sort="Taylor, Robert W" uniqKey="Taylor R" first="Robert W." last="Taylor">Robert W. Taylor</name><affiliation><nlm:aff id="aff2">Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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 <italic>TRMT10C</italic> (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 m<sup>1</sup>R9 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 <italic>TRMT10C</italic> 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 <italic>TRMT10C</italic>. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m<sup>1</sup>R9 methyltransferase activity, identifying mutations in <italic>TRMT10C</italic> as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.</p></div></front></TEI><pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27132592</article-id><article-id pub-id-type="pmc">4863561</article-id><article-id pub-id-type="publisher-id">S0002-9297(16)30045-3</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2016.03.010</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Recessive Mutations in <italic>TRMT10C</italic> Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Metodiev</surname><given-names>Metodi D.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Thompson</surname><given-names>Kyle</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Alston</surname><given-names>Charlotte L.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Morris</surname><given-names>Andrew A.M.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>He</surname><given-names>Langping</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Assouline</surname><given-names>Zarah</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Rio</surname><given-names>Marlène</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Bahi-Buisson</surname><given-names>Nadia</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Pyle</surname><given-names>Angela</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Griffin</surname><given-names>Helen</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Siira</surname><given-names>Stefan</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Filipovska</surname><given-names>Aleksandra</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Munnich</surname><given-names>Arnold</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Chinnery</surname><given-names>Patrick F.</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>McFarland</surname><given-names>Robert</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Rötig</surname><given-names>Agnès</given-names></name><email>agnes.rotig@inserm.fr</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Taylor</surname><given-names>Robert W.</given-names></name><email>robert.taylor@ncl.ac.uk</email><xref rid="aff2" ref-type="aff">2</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France</aff><aff id="aff2"><label>2</label>Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK</aff><aff id="aff3"><label>3</label>Institute of Human Development, University of Manchester, Manchester M13 9WL, UK</aff><aff id="aff4"><label>4</label>Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK</aff><aff id="aff5"><label>5</label>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France</aff><aff id="aff6"><label>6</label>Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</aff><aff id="aff7"><label>7</label>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Nedlands, WA 6009, Australia</aff><aff id="aff8"><label>8</label>Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK</aff><aff id="aff9"><label>9</label>Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>agnes.rotig@inserm.fr</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>robert.taylor@ncl.ac.uk</email></corresp><fn id="fn1"><label>10</label><p id="ntpara0010">These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="pmc-release"><day>28</day><month>4</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>05</day><month>5</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>28</day><month>4</month><year>2016</year></pub-date><volume>98</volume><issue>5</issue><fpage>993</fpage><lpage>1000</lpage><history><date date-type="received"><day>26</day><month>1</month><year>2016</year></date><date date-type="accepted"><day>14</day><month>3</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 The Authors</copyright-statement><copyright-year>2016</copyright-year><license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p></license></permissions><abstract id="abs0010"><p>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 <italic>TRMT10C</italic> (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 m<sup>1</sup>R9 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 <italic>TRMT10C</italic> 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 <italic>TRMT10C</italic>. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m<sup>1</sup>R9 methyltransferase activity, identifying mutations in <italic>TRMT10C</italic> as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.</p></abstract></article-meta><notes><p id="misc0010">Published: April 28, 2016; corrected online: June 21, 2016</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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