AustralieFrV1, Main, Exploration, bibRecord, 001107

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.

Identifieur interne : 001107 ( Main/Exploration ); précédent : 001106; suivant : 001108

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.

Auteurs : Nicole J. Lake [Australie] ; Bryn D. Webb [États-Unis] ; David A. Stroud [Australie] ; Tara R. Richman [Australie] ; Benedetta Ruzzenente [France] ; Alison G. Compton [Australie] ; Hayley S. Mountford [Royaume-Uni] ; Juliette Pulman [France] ; Coralie Zangarelli [France] ; Marlene Rio [France] ; Nathalie Bodaert [France] ; Zahra Assouline [France] ; Mingma D. Sherpa [États-Unis] ; Eric E. Schadt [États-Unis] ; Sander M. Houten [États-Unis] ; James Byrnes [États-Unis] ; Elizabeth M. Mccormick [États-Unis] ; Zarazuela Zolkipli-Cunningham [États-Unis] ; Katrina Haude [États-Unis] ; Zhancheng Zhang [États-Unis] ; Kyle Retterer [États-Unis] ; Renkui Bai [États-Unis] ; Sarah E. Calvo [États-Unis] ; Vamsi K. Mootha [États-Unis] ; John Christodoulou [Australie] ; Agnes Rötig [France] ; Aleksandra Filipovska [Australie] ; Ingrid Cristian [États-Unis] ; Marni J. Falk [États-Unis] ; Metodi D. Metodiev [France] ; David R. Thorburn [Australie]

Source :

American journal of human genetics [ 1537-6605 ] ; 2017.

RBID : pubmed:28777931

Descripteurs français

English descriptors

KwdEn :
- Adolescent, Base Sequence, Child, Child, Preschool, DNA, Mitochondrial (genetics), Exome (genetics), Female, Humans, Infant, Leigh Disease (enzymology), Leigh Disease (genetics), Male, Mitochondria (genetics), Mitochondrial Diseases (genetics), Mitochondrial Proteins (genetics), Oxidative Phosphorylation, Proteomics, RNA Splicing (genetics), Ribosomal Proteins (genetics), Ribosome Subunits, Small, Eukaryotic (genetics), Sequence Analysis, DNA.
MESH :
- chemical , genetics : DNA, Mitochondrial, Mitochondrial Proteins, Ribosomal Proteins.
- enzymology : Leigh Disease.
- genetics : Exome, Leigh Disease, Mitochondria, Mitochondrial Diseases, RNA Splicing, Ribosome Subunits, Small, Eukaryotic.
- Adolescent, Base Sequence, Child, Child, Preschool, Female, Humans, Infant, Male, Oxidative Phosphorylation, Proteomics, Sequence Analysis, DNA.

Abstract

The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322-10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32(∗)]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.

DOI: 10.1016/j.ajhg.2017.07.005
PubMed: 28777931

Affiliations:

Le document en format XML

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<author><name sortKey="Mountford, Hayley S" sort="Mountford, Hayley S" uniqKey="Mountford H" first="Hayley S" last="Mountford">Hayley S. Mountford</name>
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<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Biological and Medical Sciences, Faculty of Health Sciences, Oxford Brookes University, Oxford OX3 0BP</wicri:regionArea>
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<author><name sortKey="Bodaert, Nathalie" sort="Bodaert, Nathalie" uniqKey="Bodaert N" first="Nathalie" last="Bodaert">Nathalie Bodaert</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Pediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HP, University René Descartes, PRES Sorbonne Paris Cité, INSERM U1000 and UMR 1163, Institut Imagine, 75015 Paris</wicri:regionArea>
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<author><name sortKey="Assouline, Zahra" sort="Assouline, Zahra" uniqKey="Assouline Z" first="Zahra" last="Assouline">Zahra Assouline</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Sherpa, Mingma D" sort="Sherpa, Mingma D" uniqKey="Sherpa M" first="Mingma D" last="Sherpa">Mingma D. Sherpa</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Houten, Sander M" sort="Houten, Sander M" uniqKey="Houten S" first="Sander M" last="Houten">Sander M. Houten</name>
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<author><name sortKey="Byrnes, James" sort="Byrnes, James" uniqKey="Byrnes J" first="James" last="Byrnes">James Byrnes</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Mccormick, Elizabeth M" sort="Mccormick, Elizabeth M" uniqKey="Mccormick E" first="Elizabeth M" last="Mccormick">Elizabeth M. Mccormick</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zolkipli Cunningham, Zarazuela" sort="Zolkipli Cunningham, Zarazuela" uniqKey="Zolkipli Cunningham Z" first="Zarazuela" last="Zolkipli-Cunningham">Zarazuela Zolkipli-Cunningham</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Haude, Katrina" sort="Haude, Katrina" uniqKey="Haude K" first="Katrina" last="Haude">Katrina Haude</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zhang, Zhancheng" sort="Zhang, Zhancheng" uniqKey="Zhang Z" first="Zhancheng" last="Zhang">Zhancheng Zhang</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Retterer, Kyle" sort="Retterer, Kyle" uniqKey="Retterer K" first="Kyle" last="Retterer">Kyle Retterer</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bai, Renkui" sort="Bai, Renkui" uniqKey="Bai R" first="Renkui" last="Bai">Renkui Bai</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Calvo, Sarah E" sort="Calvo, Sarah E" uniqKey="Calvo S" first="Sarah E" last="Calvo">Sarah E. Calvo</name>
<affiliation wicri:level="2"><nlm:affiliation>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mootha, Vamsi K" sort="Mootha, Vamsi K" uniqKey="Mootha V" first="Vamsi K" last="Mootha">Vamsi K. Mootha</name>
<affiliation wicri:level="2"><nlm:affiliation>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnes" last="Rötig">Agnes Rötig</name>
<affiliation wicri:level="1"><nlm:affiliation>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris</wicri:regionArea>
<wicri:noRegion>75015 Paris</wicri:noRegion>
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</placeName>
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</author>
<author><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia; School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia; School of Molecular Sciences, University of Western Australia, Crawley, WA 6009</wicri:regionArea>
<wicri:noRegion>WA 6009</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cristian, Ingrid" sort="Cristian, Ingrid" uniqKey="Cristian I" first="Ingrid" last="Cristian">Ingrid Cristian</name>
<affiliation wicri:level="2"><nlm:affiliation>Nemours Children's Hospital, Orlando, FL 32827, USA; Division of Genetics, Arnold Palmer Hospital for Children, Orlando, FL 32806, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Nemours Children's Hospital, Orlando, FL 32827, USA; Division of Genetics, Arnold Palmer Hospital for Children, Orlando, FL 32806</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Falk, Marni J" sort="Falk, Marni J" uniqKey="Falk M" first="Marni J" last="Falk">Marni J. Falk</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Metodiev, Metodi D" sort="Metodiev, Metodi D" uniqKey="Metodiev M" first="Metodi D" last="Metodiev">Metodi D. Metodiev</name>
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</placeName>
</affiliation>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, VIC 3052</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.</title>
<author><name sortKey="Lake, Nicole J" sort="Lake, Nicole J" uniqKey="Lake N" first="Nicole J" last="Lake">Nicole J. Lake</name>
<affiliation wicri:level="4"><nlm:affiliation>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
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<orgName type="university">Université de Melbourne</orgName>
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</affiliation>
</author>
<author><name sortKey="Webb, Bryn D" sort="Webb, Bryn D" uniqKey="Webb B" first="Bryn D" last="Webb">Bryn D. Webb</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
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<author><name sortKey="Stroud, David A" sort="Stroud, David A" uniqKey="Stroud D" first="David A" last="Stroud">David A. Stroud</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC 3800</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Richman, Tara R" sort="Richman, Tara R" uniqKey="Richman T" first="Tara R" last="Richman">Tara R. Richman</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009</wicri:regionArea>
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</affiliation>
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<author><name sortKey="Ruzzenente, Benedetta" sort="Ruzzenente, Benedetta" uniqKey="Ruzzenente B" first="Benedetta" last="Ruzzenente">Benedetta Ruzzenente</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Compton, Alison G" sort="Compton, Alison G" uniqKey="Compton A" first="Alison G" last="Compton">Alison G. Compton</name>
<affiliation wicri:level="4"><nlm:affiliation>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052</wicri:regionArea>
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<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mountford, Hayley S" sort="Mountford, Hayley S" uniqKey="Mountford H" first="Hayley S" last="Mountford">Hayley S. Mountford</name>
<affiliation wicri:level="4"><nlm:affiliation>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Biological and Medical Sciences, Faculty of Health Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Biological and Medical Sciences, Faculty of Health Sciences, Oxford Brookes University, Oxford OX3 0BP</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
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<author><name sortKey="Pulman, Juliette" sort="Pulman, Juliette" uniqKey="Pulman J" first="Juliette" last="Pulman">Juliette Pulman</name>
<affiliation wicri:level="1"><nlm:affiliation>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris</wicri:regionArea>
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<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zangarelli, Coralie" sort="Zangarelli, Coralie" uniqKey="Zangarelli C" first="Coralie" last="Zangarelli">Coralie Zangarelli</name>
<affiliation wicri:level="1"><nlm:affiliation>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris</wicri:regionArea>
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<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rio, Marlene" sort="Rio, Marlene" uniqKey="Rio M" first="Marlene" last="Rio">Marlene Rio</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris</wicri:regionArea>
<wicri:noRegion>75015 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
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<author><name sortKey="Bodaert, Nathalie" sort="Bodaert, Nathalie" uniqKey="Bodaert N" first="Nathalie" last="Bodaert">Nathalie Bodaert</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Pediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HP, University René Descartes, PRES Sorbonne Paris Cité, INSERM U1000 and UMR 1163, Institut Imagine, 75015 Paris</wicri:regionArea>
<wicri:noRegion>75015 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Assouline, Zahra" sort="Assouline, Zahra" uniqKey="Assouline Z" first="Zahra" last="Assouline">Zahra Assouline</name>
<affiliation wicri:level="1"><nlm:affiliation>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Departments of Pediatric, Neurology and Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris</wicri:regionArea>
<wicri:noRegion>75015 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sherpa, Mingma D" sort="Sherpa, Mingma D" uniqKey="Sherpa M" first="Mingma D" last="Sherpa">Mingma D. Sherpa</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E" last="Schadt">Eric E. Schadt</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Houten, Sander M" sort="Houten, Sander M" uniqKey="Houten S" first="Sander M" last="Houten">Sander M. Houten</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Byrnes, James" sort="Byrnes, James" uniqKey="Byrnes J" first="James" last="Byrnes">James Byrnes</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mccormick, Elizabeth M" sort="Mccormick, Elizabeth M" uniqKey="Mccormick E" first="Elizabeth M" last="Mccormick">Elizabeth M. Mccormick</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zolkipli Cunningham, Zarazuela" sort="Zolkipli Cunningham, Zarazuela" uniqKey="Zolkipli Cunningham Z" first="Zarazuela" last="Zolkipli-Cunningham">Zarazuela Zolkipli-Cunningham</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Haude, Katrina" sort="Haude, Katrina" uniqKey="Haude K" first="Katrina" last="Haude">Katrina Haude</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zhang, Zhancheng" sort="Zhang, Zhancheng" uniqKey="Zhang Z" first="Zhancheng" last="Zhang">Zhancheng Zhang</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Retterer, Kyle" sort="Retterer, Kyle" uniqKey="Retterer K" first="Kyle" last="Retterer">Kyle Retterer</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bai, Renkui" sort="Bai, Renkui" uniqKey="Bai R" first="Renkui" last="Bai">Renkui Bai</name>
<affiliation wicri:level="2"><nlm:affiliation>GeneDx, Gaithersburg, MD 20877, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>GeneDx, Gaithersburg, MD 20877</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Calvo, Sarah E" sort="Calvo, Sarah E" uniqKey="Calvo S" first="Sarah E" last="Calvo">Sarah E. Calvo</name>
<affiliation wicri:level="2"><nlm:affiliation>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mootha, Vamsi K" sort="Mootha, Vamsi K" uniqKey="Mootha V" first="Vamsi K" last="Mootha">Vamsi K. Mootha</name>
<affiliation wicri:level="2"><nlm:affiliation>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name>
<affiliation wicri:level="4"><nlm:affiliation>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnes" last="Rötig">Agnes Rötig</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris</wicri:regionArea>
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<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia; School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia; School of Molecular Sciences, University of Western Australia, Crawley, WA 6009</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Cristian, Ingrid" sort="Cristian, Ingrid" uniqKey="Cristian I" first="Ingrid" last="Cristian">Ingrid Cristian</name>
<affiliation wicri:level="2"><nlm:affiliation>Nemours Children's Hospital, Orlando, FL 32827, USA; Division of Genetics, Arnold Palmer Hospital for Children, Orlando, FL 32806, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Nemours Children's Hospital, Orlando, FL 32827, USA; Division of Genetics, Arnold Palmer Hospital for Children, Orlando, FL 32806</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Falk, Marni J" sort="Falk, Marni J" uniqKey="Falk M" first="Marni J" last="Falk">Marni J. Falk</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Metodiev, Metodi D" sort="Metodiev, Metodi D" uniqKey="Metodiev M" first="Metodi D" last="Metodiev">Metodi D. Metodiev</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Thorburn, David R" sort="Thorburn, David R" uniqKey="Thorburn D" first="David R" last="Thorburn">David R. Thorburn</name>
<affiliation wicri:level="4"><nlm:affiliation>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address: david.thorburn@mcri.edu.au.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, VIC 3052</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">American journal of human genetics</title>
<idno type="eISSN">1537-6605</idno>
<imprint><date when="2017" type="published">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term>
<term>Base Sequence</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>DNA, Mitochondrial (genetics)</term>
<term>Exome (genetics)</term>
<term>Female</term>
<term>Humans</term>
<term>Infant</term>
<term>Leigh Disease (enzymology)</term>
<term>Leigh Disease (genetics)</term>
<term>Male</term>
<term>Mitochondria (genetics)</term>
<term>Mitochondrial Diseases (genetics)</term>
<term>Mitochondrial Proteins (genetics)</term>
<term>Oxidative Phosphorylation</term>
<term>Proteomics</term>
<term>RNA Splicing (genetics)</term>
<term>Ribosomal Proteins (genetics)</term>
<term>Ribosome Subunits, Small, Eukaryotic (genetics)</term>
<term>Sequence Analysis, DNA</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ADN mitochondrial (génétique)</term>
<term>Adolescent</term>
<term>Analyse de séquence d'ADN</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Exome (génétique)</term>
<term>Femelle</term>
<term>Humains</term>
<term>Maladie de Leigh (enzymologie)</term>
<term>Maladie de Leigh (génétique)</term>
<term>Maladies mitochondriales (génétique)</term>
<term>Mitochondries (génétique)</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Petite sous-unité du ribosome des eucaryotes (génétique)</term>
<term>Phosphorylation oxydative</term>
<term>Protéines mitochondriales (génétique)</term>
<term>Protéines ribosomiques (génétique)</term>
<term>Protéomique</term>
<term>Séquence nucléotidique</term>
<term>Épissage des ARN (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, Mitochondrial</term>
<term>Mitochondrial Proteins</term>
<term>Ribosomal Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Maladie de Leigh</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Leigh Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Exome</term>
<term>Leigh Disease</term>
<term>Mitochondria</term>
<term>Mitochondrial Diseases</term>
<term>RNA Splicing</term>
<term>Ribosome Subunits, Small, Eukaryotic</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ADN mitochondrial</term>
<term>Exome</term>
<term>Maladie de Leigh</term>
<term>Maladies mitochondriales</term>
<term>Mitochondries</term>
<term>Petite sous-unité du ribosome des eucaryotes</term>
<term>Protéines mitochondriales</term>
<term>Protéines ribosomiques</term>
<term>Épissage des ARN</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adolescent</term>
<term>Base Sequence</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Oxidative Phosphorylation</term>
<term>Proteomics</term>
<term>Sequence Analysis, DNA</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term>
<term>Analyse de séquence d'ADN</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Phosphorylation oxydative</term>
<term>Protéomique</term>
<term>Séquence nucléotidique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322-10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32(∗)]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Floride</li>
<li>Maryland</li>
<li>Massachusetts</li>
<li>Pennsylvanie</li>
<li>Victoria (État)</li>
<li>État de New York</li>
<li>Île-de-France</li>
</region>
<settlement><li>Melbourne</li>
<li>Paris</li>
</settlement>
<orgName><li>Université de Melbourne</li>
</orgName>
</list>
<tree><country name="Australie"><region name="Victoria (État)"><name sortKey="Lake, Nicole J" sort="Lake, Nicole J" uniqKey="Lake N" first="Nicole J" last="Lake">Nicole J. Lake</name>
</region>
<name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name>
<name sortKey="Compton, Alison G" sort="Compton, Alison G" uniqKey="Compton A" first="Alison G" last="Compton">Alison G. Compton</name>
<name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name>
<name sortKey="Richman, Tara R" sort="Richman, Tara R" uniqKey="Richman T" first="Tara R" last="Richman">Tara R. Richman</name>
<name sortKey="Stroud, David A" sort="Stroud, David A" uniqKey="Stroud D" first="David A" last="Stroud">David A. Stroud</name>
<name sortKey="Thorburn, David R" sort="Thorburn, David R" uniqKey="Thorburn D" first="David R" last="Thorburn">David R. Thorburn</name>
</country>
<country name="États-Unis"><region name="État de New York"><name sortKey="Webb, Bryn D" sort="Webb, Bryn D" uniqKey="Webb B" first="Bryn D" last="Webb">Bryn D. Webb</name>
</region>
<name sortKey="Bai, Renkui" sort="Bai, Renkui" uniqKey="Bai R" first="Renkui" last="Bai">Renkui Bai</name>
<name sortKey="Byrnes, James" sort="Byrnes, James" uniqKey="Byrnes J" first="James" last="Byrnes">James Byrnes</name>
<name sortKey="Calvo, Sarah E" sort="Calvo, Sarah E" uniqKey="Calvo S" first="Sarah E" last="Calvo">Sarah E. Calvo</name>
<name sortKey="Cristian, Ingrid" sort="Cristian, Ingrid" uniqKey="Cristian I" first="Ingrid" last="Cristian">Ingrid Cristian</name>
<name sortKey="Falk, Marni J" sort="Falk, Marni J" uniqKey="Falk M" first="Marni J" last="Falk">Marni J. Falk</name>
<name sortKey="Haude, Katrina" sort="Haude, Katrina" uniqKey="Haude K" first="Katrina" last="Haude">Katrina Haude</name>
<name sortKey="Houten, Sander M" sort="Houten, Sander M" uniqKey="Houten S" first="Sander M" last="Houten">Sander M. Houten</name>
<name sortKey="Mccormick, Elizabeth M" sort="Mccormick, Elizabeth M" uniqKey="Mccormick E" first="Elizabeth M" last="Mccormick">Elizabeth M. Mccormick</name>
<name sortKey="Mootha, Vamsi K" sort="Mootha, Vamsi K" uniqKey="Mootha V" first="Vamsi K" last="Mootha">Vamsi K. Mootha</name>
<name sortKey="Retterer, Kyle" sort="Retterer, Kyle" uniqKey="Retterer K" first="Kyle" last="Retterer">Kyle Retterer</name>
<name sortKey="Schadt, Eric E" sort="Schadt, Eric E" uniqKey="Schadt E" first="Eric E" last="Schadt">Eric E. Schadt</name>
<name sortKey="Sherpa, Mingma D" sort="Sherpa, Mingma D" uniqKey="Sherpa M" first="Mingma D" last="Sherpa">Mingma D. Sherpa</name>
<name sortKey="Zhang, Zhancheng" sort="Zhang, Zhancheng" uniqKey="Zhang Z" first="Zhancheng" last="Zhang">Zhancheng Zhang</name>
<name sortKey="Zolkipli Cunningham, Zarazuela" sort="Zolkipli Cunningham, Zarazuela" uniqKey="Zolkipli Cunningham Z" first="Zarazuela" last="Zolkipli-Cunningham">Zarazuela Zolkipli-Cunningham</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Ruzzenente, Benedetta" sort="Ruzzenente, Benedetta" uniqKey="Ruzzenente B" first="Benedetta" last="Ruzzenente">Benedetta Ruzzenente</name>
</region>
<name sortKey="Assouline, Zahra" sort="Assouline, Zahra" uniqKey="Assouline Z" first="Zahra" last="Assouline">Zahra Assouline</name>
<name sortKey="Bodaert, Nathalie" sort="Bodaert, Nathalie" uniqKey="Bodaert N" first="Nathalie" last="Bodaert">Nathalie Bodaert</name>
<name sortKey="Metodiev, Metodi D" sort="Metodiev, Metodi D" uniqKey="Metodiev M" first="Metodi D" last="Metodiev">Metodi D. Metodiev</name>
<name sortKey="Pulman, Juliette" sort="Pulman, Juliette" uniqKey="Pulman J" first="Juliette" last="Pulman">Juliette Pulman</name>
<name sortKey="Rio, Marlene" sort="Rio, Marlene" uniqKey="Rio M" first="Marlene" last="Rio">Marlene Rio</name>
<name sortKey="Rotig, Agnes" sort="Rotig, Agnes" uniqKey="Rotig A" first="Agnes" last="Rötig">Agnes Rötig</name>
<name sortKey="Zangarelli, Coralie" sort="Zangarelli, Coralie" uniqKey="Zangarelli C" first="Coralie" last="Zangarelli">Coralie Zangarelli</name>
</country>
<country name="Royaume-Uni"><region name="Victoria (État)"><name sortKey="Mountford, Hayley S" sort="Mountford, Hayley S" uniqKey="Mountford H" first="Hayley S" last="Mountford">Hayley S. Mountford</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.

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