Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia
Identifieur interne : 001519 ( Pmc/Curation ); précédent : 001518; suivant : 001520Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia
Auteurs : Lisa G. Riley [Australie] ; Minal J. Menezes [Australie] ; Joëlle Rudinger-Thirion [France] ; Rachael Duff [Australie] ; Pascale De Lonlay [France] ; Agnes Rotig [France] ; Michel C. Tchan [Australie] ; Mark Davis [Australie] ; Sandra T. Cooper [Australie] ; John Christodoulou [Australie]Source :
- Orphanet Journal of Rare Diseases [ 1750-1172 ] ; 2013.
Abstract
Mutations in the mitochondrial tyrosyl-tRNA synthetase (
Twelve patients were screened for
Pathogenic
In this study we have identified novel
Url:
DOI: 10.1186/1750-1172-8-193
PubMed: 24344687
PubMed Central: 3878580
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Phenotypic variability and identification of novel <italic>YARS2</italic>
mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia</title>
<author><name sortKey="Riley, Lisa G" sort="Riley, Lisa G" uniqKey="Riley L" first="Lisa G" last="Riley">Lisa G. Riley</name>
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<country xml:lang="fr">Australie</country>
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<author><name sortKey="Menezes, Minal J" sort="Menezes, Minal J" uniqKey="Menezes M" first="Minal J" last="Menezes">Minal J. Menezes</name>
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<country xml:lang="fr">Australie</country>
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<author><name sortKey="Rudinger Thirion, Joelle" sort="Rudinger Thirion, Joelle" uniqKey="Rudinger Thirion J" first="Joëlle" last="Rudinger-Thirion">Joëlle Rudinger-Thirion</name>
<affiliation wicri:level="1"><nlm:aff id="I4">Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg 67084, France</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Duff, Rachael" sort="Duff, Rachael" uniqKey="Duff R" first="Rachael" last="Duff">Rachael Duff</name>
<affiliation wicri:level="1"><nlm:aff id="I5">Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009</wicri:regionArea>
</affiliation>
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<author><name sortKey="De Lonlay, Pascale" sort="De Lonlay, Pascale" uniqKey="De Lonlay P" first="Pascale" last="De Lonlay">Pascale De Lonlay</name>
<affiliation wicri:level="1"><nlm:aff id="I6">Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015</wicri:regionArea>
</affiliation>
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<author><name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnes" last="Rotig">Agnes Rotig</name>
<affiliation wicri:level="1"><nlm:aff id="I6">Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tchan, Michel C" sort="Tchan, Michel C" uniqKey="Tchan M" first="Michel C" last="Tchan">Michel C. Tchan</name>
<affiliation wicri:level="1"><nlm:aff id="I3">Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I7">Department of Genetic Medicine, Westmead Hospital, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Genetic Medicine, Westmead Hospital, Sydney</wicri:regionArea>
</affiliation>
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<author><name sortKey="Davis, Mark" sort="Davis, Mark" uniqKey="Davis M" first="Mark" last="Davis">Mark Davis</name>
<affiliation wicri:level="1"><nlm:aff id="I8">Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cooper, Sandra T" sort="Cooper, Sandra T" uniqKey="Cooper S" first="Sandra T" last="Cooper">Sandra T. Cooper</name>
<affiliation wicri:level="1"><nlm:aff id="I2">Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I9">Institute for Neuroscience and Muscle Research, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I2">Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I3">Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I10">Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145</wicri:regionArea>
</affiliation>
</author>
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<series><title level="j">Orphanet Journal of Rare Diseases</title>
<idno type="eISSN">1750-1172</idno>
<imprint><date when="2013">2013</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Mutations in the mitochondrial tyrosyl-tRNA synthetase (<italic>YARS2</italic>
) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in <italic>YARS2</italic>
.</p>
</sec>
<sec><title>Methods</title>
<p>Twelve patients were screened for <italic>YARS2</italic>
mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects.</p>
</sec>
<sec><title>Results</title>
<p>Pathogenic<italic>YARS2</italic>
mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel <italic>YARS2</italic>
mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism.</p>
</sec>
<sec><title>Conclusion</title>
<p>In this study we have identified novel <italic>YARS2</italic>
mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article" xml:lang="en"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Orphanet J Rare Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Orphanet J Rare Dis</journal-id>
<journal-title-group><journal-title>Orphanet Journal of Rare Diseases</journal-title>
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<issn pub-type="epub">1750-1172</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
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<article-meta><article-id pub-id-type="pmid">24344687</article-id>
<article-id pub-id-type="pmc">3878580</article-id>
<article-id pub-id-type="publisher-id">1750-1172-8-193</article-id>
<article-id pub-id-type="doi">10.1186/1750-1172-8-193</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
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<title-group><article-title>Phenotypic variability and identification of novel <italic>YARS2</italic>
mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia</article-title>
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<email>lisa.riley@health.nsw.gov.au</email>
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<aff id="I1"><label>1</label>
Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney, Australia</aff>
<aff id="I2"><label>2</label>
Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney, Australia</aff>
<aff id="I3"><label>3</label>
Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney, Australia</aff>
<aff id="I4"><label>4</label>
Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg 67084, France</aff>
<aff id="I5"><label>5</label>
Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia</aff>
<aff id="I6"><label>6</label>
Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015, France</aff>
<aff id="I7"><label>7</label>
Department of Genetic Medicine, Westmead Hospital, Sydney, Australia</aff>
<aff id="I8"><label>8</label>
Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia</aff>
<aff id="I9"><label>9</label>
Institute for Neuroscience and Muscle Research, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney, Australia</aff>
<aff id="I10"><label>10</label>
Western Sydney Genetics Program, Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia</aff>
<pub-date pub-type="collection"><year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>12</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<fpage>193</fpage>
<lpage>193</lpage>
<history><date date-type="received"><day>16</day>
<month>8</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>13</day>
<month>12</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2013 Riley et al.; licensee BioMed Central Ltd.</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>Riley et al.; licensee BioMed Central Ltd.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri xlink:href="http://www.ojrd.com/content/8/1/193"></self-uri>
<abstract><sec><title>Background</title>
<p>Mutations in the mitochondrial tyrosyl-tRNA synthetase (<italic>YARS2</italic>
) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in <italic>YARS2</italic>
.</p>
</sec>
<sec><title>Methods</title>
<p>Twelve patients were screened for <italic>YARS2</italic>
mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects.</p>
</sec>
<sec><title>Results</title>
<p>Pathogenic<italic>YARS2</italic>
mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel <italic>YARS2</italic>
mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism.</p>
</sec>
<sec><title>Conclusion</title>
<p>In this study we have identified novel <italic>YARS2</italic>
mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.</p>
</sec>
</abstract>
<kwd-group><kwd>Mitochondrial respiratory chain</kwd>
<kwd>Myopathy with lactic acidosis and sideroblastic anemia</kwd>
<kwd>Aminoacyl tRNA-synthetase</kwd>
<kwd>Mitochondrial myopathies</kwd>
<kwd>Muscle diseases</kwd>
<kwd>Lactic acidaemia</kwd>
<kwd>Inborn error of metabolism</kwd>
<kwd>Mutation</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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