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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, <italic>YARS2</italic>, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome</title><author><name sortKey="Riley, Lisa G" sort="Riley, Lisa G" uniqKey="Riley L" first="Lisa G." last="Riley">Lisa G. Riley</name><affiliation><nlm:aff id="aff1">Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Cooper, Sandra" sort="Cooper, Sandra" uniqKey="Cooper S" first="Sandra" last="Cooper">Sandra Cooper</name><affiliation><nlm:aff id="aff2">Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia</nlm:aff></affiliation></author><author><name sortKey="Hickey, Peter" sort="Hickey, Peter" uniqKey="Hickey P" first="Peter" last="Hickey">Peter Hickey</name><affiliation><nlm:aff id="aff4">Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia</nlm:aff></affiliation></author><author><name sortKey="Rudinger Thirion, Joelle" sort="Rudinger Thirion, Joelle" uniqKey="Rudinger Thirion J" first="Joëlle" last="Rudinger-Thirion">Joëlle Rudinger-Thirion</name><affiliation><nlm:aff id="aff5">Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France</nlm:aff></affiliation></author><author><name sortKey="Mckenzie, Matthew" sort="Mckenzie, Matthew" uniqKey="Mckenzie M" first="Matthew" last="Mckenzie">Matthew Mckenzie</name><affiliation><nlm:aff id="aff6">Department of Biochemistry, La Trobe University, Melbourne 3086, Australia</nlm:aff></affiliation></author><author><name sortKey="Compton, Alison" sort="Compton, Alison" uniqKey="Compton A" first="Alison" last="Compton">Alison Compton</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Lim, Sze Chern" sort="Lim, Sze Chern" uniqKey="Lim S" first="Sze Chern" last="Lim">Sze Chern Lim</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Thorburn, David" sort="Thorburn, David" uniqKey="Thorburn D" first="David" last="Thorburn">David Thorburn</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Ryan, Michael T" sort="Ryan, Michael T" uniqKey="Ryan M" first="Michael T." last="Ryan">Michael T. Ryan</name><affiliation><nlm:aff id="aff6">Department of Biochemistry, La Trobe University, Melbourne 3086, Australia</nlm:aff></affiliation></author><author><name sortKey="Giege, Richard" sort="Giege, Richard" uniqKey="Giege R" first="Richard" last="Giegé">Richard Giegé</name><affiliation><nlm:aff id="aff5">Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France</nlm:aff></affiliation></author><author><name sortKey="Bahlo, Melanie" sort="Bahlo, Melanie" uniqKey="Bahlo M" first="Melanie" last="Bahlo">Melanie Bahlo</name><affiliation><nlm:aff id="aff4">Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia</nlm:aff></affiliation></author><author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name><affiliation><nlm:aff id="aff1">Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Discipline of Genetic Medicine, University of Sydney, Sydney 2006, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20598274</idno><idno type="pmc">2896778</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896778</idno><idno type="RBID">PMC:2896778</idno><idno type="doi">10.1016/j.ajhg.2010.06.001</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">001699</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001699</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, <italic>YARS2</italic>, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome</title><author><name sortKey="Riley, Lisa G" sort="Riley, Lisa G" uniqKey="Riley L" first="Lisa G." last="Riley">Lisa G. Riley</name><affiliation><nlm:aff id="aff1">Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Cooper, Sandra" sort="Cooper, Sandra" uniqKey="Cooper S" first="Sandra" last="Cooper">Sandra Cooper</name><affiliation><nlm:aff id="aff2">Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia</nlm:aff></affiliation></author><author><name sortKey="Hickey, Peter" sort="Hickey, Peter" uniqKey="Hickey P" first="Peter" last="Hickey">Peter Hickey</name><affiliation><nlm:aff id="aff4">Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia</nlm:aff></affiliation></author><author><name sortKey="Rudinger Thirion, Joelle" sort="Rudinger Thirion, Joelle" uniqKey="Rudinger Thirion J" first="Joëlle" last="Rudinger-Thirion">Joëlle Rudinger-Thirion</name><affiliation><nlm:aff id="aff5">Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France</nlm:aff></affiliation></author><author><name sortKey="Mckenzie, Matthew" sort="Mckenzie, Matthew" uniqKey="Mckenzie M" first="Matthew" last="Mckenzie">Matthew Mckenzie</name><affiliation><nlm:aff id="aff6">Department of Biochemistry, La Trobe University, Melbourne 3086, Australia</nlm:aff></affiliation></author><author><name sortKey="Compton, Alison" sort="Compton, Alison" uniqKey="Compton A" first="Alison" last="Compton">Alison Compton</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Lim, Sze Chern" sort="Lim, Sze Chern" uniqKey="Lim S" first="Sze Chern" last="Lim">Sze Chern Lim</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Thorburn, David" sort="Thorburn, David" uniqKey="Thorburn D" first="David" last="Thorburn">David Thorburn</name><affiliation><nlm:aff id="aff7">Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia</nlm:aff></affiliation></author><author><name sortKey="Ryan, Michael T" sort="Ryan, Michael T" uniqKey="Ryan M" first="Michael T." last="Ryan">Michael T. Ryan</name><affiliation><nlm:aff id="aff6">Department of Biochemistry, La Trobe University, Melbourne 3086, Australia</nlm:aff></affiliation></author><author><name sortKey="Giege, Richard" sort="Giege, Richard" uniqKey="Giege R" first="Richard" last="Giegé">Richard Giegé</name><affiliation><nlm:aff id="aff5">Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France</nlm:aff></affiliation></author><author><name sortKey="Bahlo, Melanie" sort="Bahlo, Melanie" uniqKey="Bahlo M" first="Melanie" last="Bahlo">Melanie Bahlo</name><affiliation><nlm:aff id="aff4">Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia</nlm:aff></affiliation></author><author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name><affiliation><nlm:aff id="aff1">Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Discipline of Genetic Medicine, University of Sydney, Sydney 2006, Australia</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="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in <italic>YARS2</italic>, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The <italic>YARS2</italic> gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with <italic>PUS1</italic> mutations; hence, the <italic>YARS2</italic> mutation reported here is an alternative cause of MLASA.</p></div></front></TEI><pmc article-type="research-article"><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-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">20598274</article-id><article-id pub-id-type="pmc">2896778</article-id><article-id pub-id-type="publisher-id">AJHG675</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2010.06.001</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, <italic>YARS2</italic>, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Riley</surname><given-names>Lisa G.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Sandra</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Hickey</surname><given-names>Peter</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Rudinger-Thirion</surname><given-names>Joëlle</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>McKenzie</surname><given-names>Matthew</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Compton</surname><given-names>Alison</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Lim</surname><given-names>Sze Chern</given-names></name><xref rid="aff7" ref-type="aff">7</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Thorburn</surname><given-names>David</given-names></name><xref rid="aff7" ref-type="aff">7</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Ryan</surname><given-names>Michael T.</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Giegé</surname><given-names>Richard</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Bahlo</surname><given-names>Melanie</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Christodoulou</surname><given-names>John</given-names></name><email>johnc@chw.edu.au</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff9" ref-type="aff">9</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia</aff><aff id="aff2"><label>2</label>Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney 2145, Australia</aff><aff id="aff3"><label>3</label>Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia</aff><aff id="aff4"><label>4</label>Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia</aff><aff id="aff5"><label>5</label>Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France</aff><aff id="aff6"><label>6</label>Department of Biochemistry, La Trobe University, Melbourne 3086, Australia</aff><aff id="aff7"><label>7</label>Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia</aff><aff id="aff8"><label>8</label>Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia</aff><aff id="aff9"><label>9</label>Discipline of Genetic Medicine, University of Sydney, Sydney 2006, Australia</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>johnc@chw.edu.au</email></corresp></author-notes><pub-date pub-type="ppub"><day>09</day><month>7</month><year>2010</year></pub-date><volume>87</volume><issue>1</issue><fpage>52</fpage><lpage>59</lpage><history><date date-type="received"><day>25</day><month>4</month><year>2010</year></date><date date-type="rev-recd"><day>26</day><month>5</month><year>2010</year></date><date date-type="accepted"><day>8</day><month>6</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in <italic>YARS2</italic>, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The <italic>YARS2</italic> gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with <italic>PUS1</italic> mutations; hence, the <italic>YARS2</italic> mutation reported here is an alternative cause of MLASA.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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