AustralieFrV1, Ncbi, Curation, bibRecord, 000823

Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome

Identifieur interne : 000823 ( Ncbi/Curation ); précédent : 000822; suivant : 000824

Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome

Auteurs : Lisa G. Riley [Australie] ; Sandra Cooper [Australie] ; Peter Hickey [Australie] ; Joëlle Rudinger-Thirion [France] ; Matthew Mckenzie [Australie] ; Alison Compton [Australie] ; Sze Chern Lim [Australie] ; David Thorburn [Australie] ; Michael T. Ryan [Australie] ; Richard Giegé [France] ; Melanie Bahlo [Australie] ; John Christodoulou [Australie]

Source :

American Journal of Human Genetics [ 0002-9297 ] ; 2010.

RBID : PMC:2896778

Abstract

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 YARS2, 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 YARS2 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 PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896778

DOI: 10.1016/j.ajhg.2010.06.001
PubMed: 20598274
PubMed Central: 2896778

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PMC:2896778

Le document en format XML

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, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome</title>
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<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>
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<author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name>
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<wicri:regionArea>Discipline of Genetic Medicine, University of Sydney, Sydney 2006</wicri:regionArea>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
<settlement type="city">Sydney</settlement>
</placeName>
<orgName type="university">Université de Sydney</orgName>
</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>
</record>

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Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome

Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome

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