AustralieFrV1, Main, Exploration, bibRecord, 002513

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Identifieur interne : 002513 ( Main/Exploration ); précédent : 002512; suivant : 002514

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Auteurs : Gali Heimer [Israël] ; Juha M. Ker T R [Finlande] ; Lisa G. Riley [Australie] ; Shanti Balasubramaniam [Australie] ; Eran Eyal [Israël] ; Laura P. Pietik Inen [Finlande] ; J. Kalervo Hiltunen [Finlande] ; Dina Marek-Yagel [Israël] ; Jeffrey Hamada [États-Unis] ; Allison Gregory [États-Unis] ; Caleb Rogers [États-Unis] ; Penelope Hogarth [États-Unis] ; Martha A. Nance [États-Unis] ; Nechama Shalva [Israël] ; Alvit Veber [Israël] ; Michal Tzadok [Israël] ; Andreea Nissenkorn [Israël] ; Davide Tonduti [Italie] ; Florence Renaldo [France] ; Ichraf Kraoua [Tunisie] ; Celeste Panteghini [Italie] ; Lorella Valletta [Italie] ; Barbara Garavaglia [Italie] ; Mark J. Cowley [Australie] ; Velimir Gayevskiy [Australie] ; Tony Roscioli [Australie] ; Jonathon M. Silberstein [Australie] ; Chen Hoffmann [Israël] ; Annick Raas-Rothschild [Israël] ; Valeria Tiranti [Italie] ; Yair Anikster [Israël] ; John Christodoulou [Australie] ; Alexander J. Kastaniotis [Finlande] ; Bruria Ben-Zeev [Israël] ; Susan J. Hayflick [États-Unis]

Source :

American Journal of Human Genetics [ 0002-9297 ] ; 2016.

RBID : PMC:5142118

Descripteurs français

English descriptors

KwdEn :
- Basal Ganglia (metabolism), Cells, Cultured, Child, Child, Preschool, Dystonic Disorders (genetics), Fatty Acids (biosynthesis), Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria (metabolism), Mitochondrial Diseases (genetics), Models, Molecular, Mutation, Mutation, Missense (genetics), Optic Atrophy (genetics), Oxidoreductases Acting on CH-CH Group Donors (chemistry), Oxidoreductases Acting on CH-CH Group Donors (genetics), Oxidoreductases Acting on CH-CH Group Donors (metabolism), Pedigree, RNA Splice Sites (genetics), Saccharomyces cerevisiae (genetics), Saccharomyces cerevisiae (metabolism).
MESH :
- chemical , biosynthesis : Fatty Acids.
- chemical , chemistry : Oxidoreductases Acting on CH-CH Group Donors.
- genetics : Dystonic Disorders, Mitochondrial Diseases, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, RNA Splice Sites, Saccharomyces cerevisiae.
- metabolism : Basal Ganglia, Mitochondria, Oxidoreductases Acting on CH-CH Group Donors, Saccharomyces cerevisiae.
- Cells, Cultured, Child, Child, Preschool, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Models, Molecular, Mutation, Pedigree.

Abstract

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285^∗), c.247_250del (p.Asn83Hisfs^∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142118

DOI: 10.1016/j.ajhg.2016.09.021
PubMed: 27817865
PubMed Central: 5142118

Affiliations:

Le document en format XML

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 Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder</title>
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<author><name sortKey="Tzadok, Michal" sort="Tzadok, Michal" uniqKey="Tzadok M" first="Michal" last="Tzadok">Michal Tzadok</name>
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<country xml:lang="fr">Israël</country>
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<author><name sortKey="Nissenkorn, Andreea" sort="Nissenkorn, Andreea" uniqKey="Nissenkorn A" first="Andreea" last="Nissenkorn">Andreea Nissenkorn</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
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</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
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<author><name sortKey="Tonduti, Davide" sort="Tonduti, Davide" uniqKey="Tonduti D" first="Davide" last="Tonduti">Davide Tonduti</name>
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<country xml:lang="fr">Italie</country>
<wicri:regionArea>Child Neurology Department, Foundation IRCCS, Neurological Institute C. Besta, 20133 Milan</wicri:regionArea>
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</placeName>
</affiliation>
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<author><name sortKey="Renaldo, Florence" sort="Renaldo, Florence" uniqKey="Renaldo F" first="Florence" last="Renaldo">Florence Renaldo</name>
<affiliation wicri:level="1"><nlm:aff id="aff15">Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris</wicri:regionArea>
<wicri:noRegion>75019 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kraoua, Ichraf" sort="Kraoua, Ichraf" uniqKey="Kraoua I" first="Ichraf" last="Kraoua">Ichraf Kraoua</name>
<affiliation wicri:level="1"><nlm:aff id="aff16">Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis</wicri:regionArea>
<placeName><settlement type="city">Tunis</settlement>
<region nuts="2">Gouvernorat de Tunis</region>
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</affiliation>
</author>
<author><name sortKey="Panteghini, Celeste" sort="Panteghini, Celeste" uniqKey="Panteghini C" first="Celeste" last="Panteghini">Celeste Panteghini</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Valletta, Lorella" sort="Valletta, Lorella" uniqKey="Valletta L" first="Lorella" last="Valletta">Lorella Valletta</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Garavaglia, Barbara" sort="Garavaglia, Barbara" uniqKey="Garavaglia B" first="Barbara" last="Garavaglia">Barbara Garavaglia</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cowley, Mark J" sort="Cowley, Mark J" uniqKey="Cowley M" first="Mark J." last="Cowley">Mark J. Cowley</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff19">St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gayevskiy, Velimir" sort="Gayevskiy, Velimir" uniqKey="Gayevskiy V" first="Velimir" last="Gayevskiy">Velimir Gayevskiy</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Roscioli, Tony" sort="Roscioli, Tony" uniqKey="Roscioli T" first="Tony" last="Roscioli">Tony Roscioli</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff19">St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Silberstein, Jonathon M" sort="Silberstein, Jonathon M" uniqKey="Silberstein J" first="Jonathon M." last="Silberstein">Jonathon M. Silberstein</name>
<affiliation wicri:level="1"><nlm:aff id="aff20">Neurology Department, Princess Margaret Hospital, Perth, WA 6000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Neurology Department, Princess Margaret Hospital, Perth, WA 6000</wicri:regionArea>
<wicri:noRegion>WA 6000</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hoffmann, Chen" sort="Hoffmann, Chen" uniqKey="Hoffmann C" first="Chen" last="Hoffmann">Chen Hoffmann</name>
<affiliation wicri:level="1"><nlm:aff id="aff21">Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Raas Rothschild, Annick" sort="Raas Rothschild, Annick" uniqKey="Raas Rothschild A" first="Annick" last="Raas-Rothschild">Annick Raas-Rothschild</name>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff22">Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tiranti, Valeria" sort="Tiranti, Valeria" uniqKey="Tiranti V" first="Valeria" last="Tiranti">Valeria Tiranti</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Anikster, Yair" sort="Anikster, Yair" uniqKey="Anikster Y" first="Yair" last="Anikster">Yair Anikster</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</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="aff4">Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff5">Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff6">Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff23">Murdoch Children’s Research Institute and Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children’s Research Institute and Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052</wicri:regionArea>
<wicri:noRegion>VIC 3052</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff24">Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>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="Kastaniotis, Alexander J" sort="Kastaniotis, Alexander J" uniqKey="Kastaniotis A" first="Alexander J." last="Kastaniotis">Alexander J. Kastaniotis</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014</wicri:regionArea>
<wicri:noRegion>Oulu 90014</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ben Zeev, Bruria" sort="Ben Zeev, Bruria" uniqKey="Ben Zeev B" first="Bruria" last="Ben-Zeev">Bruria Ben-Zeev</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hayflick, Susan J" sort="Hayflick, Susan J" uniqKey="Hayflick S" first="Susan J." last="Hayflick">Susan J. Hayflick</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff11">Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff25">Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>MECR</italic>
 Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder</title>
<author><name sortKey="Heimer, Gali" sort="Heimer, Gali" uniqKey="Heimer G" first="Gali" last="Heimer">Gali Heimer</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2">The Pinchas Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Pinchas Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ker T R, Juha M" sort="Ker T R, Juha M" uniqKey="Ker T R J" first="Juha M." last="Ker T R">Juha M. Ker T R</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014</wicri:regionArea>
<wicri:noRegion>Oulu 90014</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Riley, Lisa G" sort="Riley, Lisa G" uniqKey="Riley L" first="Lisa G." last="Riley">Lisa G. Riley</name>
<affiliation wicri:level="1"><nlm:aff id="aff4">Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff5">Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Balasubramaniam, Shanti" sort="Balasubramaniam, Shanti" uniqKey="Balasubramaniam S" first="Shanti" last="Balasubramaniam">Shanti Balasubramaniam</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff7">Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA 6000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA 6000</wicri:regionArea>
<wicri:noRegion>WA 6000</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Eyal, Eran" sort="Eyal, Eran" uniqKey="Eyal E" first="Eran" last="Eyal">Eran Eyal</name>
<affiliation wicri:level="1"><nlm:aff id="aff8">Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Pietik Inen, Laura P" sort="Pietik Inen, Laura P" uniqKey="Pietik Inen L" first="Laura P." last="Pietik Inen">Laura P. Pietik Inen</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014</wicri:regionArea>
<wicri:noRegion>Oulu 90014</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hiltunen, J Kalervo" sort="Hiltunen, J Kalervo" uniqKey="Hiltunen J" first="J. Kalervo" last="Hiltunen">J. Kalervo Hiltunen</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014</wicri:regionArea>
<wicri:noRegion>Oulu 90014</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Marek Yagel, Dina" sort="Marek Yagel, Dina" uniqKey="Marek Yagel D" first="Dina" last="Marek-Yagel">Dina Marek-Yagel</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hamada, Jeffrey" sort="Hamada, Jeffrey" uniqKey="Hamada J" first="Jeffrey" last="Hamada">Jeffrey Hamada</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Gregory, Allison" sort="Gregory, Allison" uniqKey="Gregory A" first="Allison" last="Gregory">Allison Gregory</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Rogers, Caleb" sort="Rogers, Caleb" uniqKey="Rogers C" first="Caleb" last="Rogers">Caleb Rogers</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Hogarth, Penelope" sort="Hogarth, Penelope" uniqKey="Hogarth P" first="Penelope" last="Hogarth">Penelope Hogarth</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff11">Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Nance, Martha A" sort="Nance, Martha A" uniqKey="Nance M" first="Martha A." last="Nance">Martha A. Nance</name>
<affiliation wicri:level="2"><nlm:aff id="aff12">Struthers Parkinson’s Center, Golden Valley, MN 55427, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Struthers Parkinson’s Center, Golden Valley, MN 55427</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shalva, Nechama" sort="Shalva, Nechama" uniqKey="Shalva N" first="Nechama" last="Shalva">Nechama Shalva</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Veber, Alvit" sort="Veber, Alvit" uniqKey="Veber A" first="Alvit" last="Veber">Alvit Veber</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tzadok, Michal" sort="Tzadok, Michal" uniqKey="Tzadok M" first="Michal" last="Tzadok">Michal Tzadok</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Nissenkorn, Andreea" sort="Nissenkorn, Andreea" uniqKey="Nissenkorn A" first="Andreea" last="Nissenkorn">Andreea Nissenkorn</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tonduti, Davide" sort="Tonduti, Davide" uniqKey="Tonduti D" first="Davide" last="Tonduti">Davide Tonduti</name>
<affiliation wicri:level="1"><nlm:aff id="aff14">Child Neurology Department, Foundation IRCCS, Neurological Institute C. Besta, 20133 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Child Neurology Department, Foundation IRCCS, Neurological Institute C. Besta, 20133 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Renaldo, Florence" sort="Renaldo, Florence" uniqKey="Renaldo F" first="Florence" last="Renaldo">Florence Renaldo</name>
<affiliation wicri:level="1"><nlm:aff id="aff15">Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris</wicri:regionArea>
<wicri:noRegion>75019 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kraoua, Ichraf" sort="Kraoua, Ichraf" uniqKey="Kraoua I" first="Ichraf" last="Kraoua">Ichraf Kraoua</name>
<affiliation wicri:level="1"><nlm:aff id="aff16">Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis</wicri:regionArea>
<placeName><settlement type="city">Tunis</settlement>
<region nuts="2">Gouvernorat de Tunis</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Panteghini, Celeste" sort="Panteghini, Celeste" uniqKey="Panteghini C" first="Celeste" last="Panteghini">Celeste Panteghini</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Valletta, Lorella" sort="Valletta, Lorella" uniqKey="Valletta L" first="Lorella" last="Valletta">Lorella Valletta</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Garavaglia, Barbara" sort="Garavaglia, Barbara" uniqKey="Garavaglia B" first="Barbara" last="Garavaglia">Barbara Garavaglia</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cowley, Mark J" sort="Cowley, Mark J" uniqKey="Cowley M" first="Mark J." last="Cowley">Mark J. Cowley</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff19">St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gayevskiy, Velimir" sort="Gayevskiy, Velimir" uniqKey="Gayevskiy V" first="Velimir" last="Gayevskiy">Velimir Gayevskiy</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Roscioli, Tony" sort="Roscioli, Tony" uniqKey="Roscioli T" first="Tony" last="Roscioli">Tony Roscioli</name>
<affiliation wicri:level="1"><nlm:aff id="aff18">Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff19">St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>St Vincent’s Clinical School, University of NSW, Sydney, NSW 2010</wicri:regionArea>
<wicri:noRegion>NSW 2010</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Silberstein, Jonathon M" sort="Silberstein, Jonathon M" uniqKey="Silberstein J" first="Jonathon M." last="Silberstein">Jonathon M. Silberstein</name>
<affiliation wicri:level="1"><nlm:aff id="aff20">Neurology Department, Princess Margaret Hospital, Perth, WA 6000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Neurology Department, Princess Margaret Hospital, Perth, WA 6000</wicri:regionArea>
<wicri:noRegion>WA 6000</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hoffmann, Chen" sort="Hoffmann, Chen" uniqKey="Hoffmann C" first="Chen" last="Hoffmann">Chen Hoffmann</name>
<affiliation wicri:level="1"><nlm:aff id="aff21">Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Raas Rothschild, Annick" sort="Raas Rothschild, Annick" uniqKey="Raas Rothschild A" first="Annick" last="Raas-Rothschild">Annick Raas-Rothschild</name>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff22">Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tiranti, Valeria" sort="Tiranti, Valeria" uniqKey="Tiranti V" first="Valeria" last="Tiranti">Valeria Tiranti</name>
<affiliation wicri:level="1"><nlm:aff id="aff17">Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Anikster, Yair" sort="Anikster, Yair" uniqKey="Anikster Y" first="Yair" last="Anikster">Yair Anikster</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Metabolic Disease Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</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="aff4">Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetic Metabolic Disorders Research Unit, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff5">Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff6">Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, NSW 2145</wicri:regionArea>
<wicri:noRegion>NSW 2145</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff23">Murdoch Children’s Research Institute and Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Murdoch Children’s Research Institute and Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052</wicri:regionArea>
<wicri:noRegion>VIC 3052</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff24">Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>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="Kastaniotis, Alexander J" sort="Kastaniotis, Alexander J" uniqKey="Kastaniotis A" first="Alexander J." last="Kastaniotis">Alexander J. Kastaniotis</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014</wicri:regionArea>
<wicri:noRegion>Oulu 90014</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ben Zeev, Bruria" sort="Ben Zeev, Bruria" uniqKey="Ben Zeev B" first="Bruria" last="Ben-Zeev">Bruria Ben-Zeev</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Pediatric Neurology Unit, Edmond and Lily Children’s Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan</wicri:regionArea>
<wicri:noRegion>52621 Ramat Gan</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff13">The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv</wicri:regionArea>
<wicri:noRegion>69978 Tel Aviv</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hayflick, Susan J" sort="Hayflick, Susan J" uniqKey="Hayflick S" first="Susan J." last="Hayflick">Susan J. Hayflick</name>
<affiliation wicri:level="4"><nlm:aff id="aff10">Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff11">Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff25">Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</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="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Basal Ganglia (metabolism)</term>
<term>Cells, Cultured</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Dystonic Disorders (genetics)</term>
<term>Fatty Acids (biosynthesis)</term>
<term>Female</term>
<term>Fibroblasts</term>
<term>Genetic Complementation Test</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Mitochondria (metabolism)</term>
<term>Mitochondrial Diseases (genetics)</term>
<term>Models, Molecular</term>
<term>Mutation</term>
<term>Mutation, Missense (genetics)</term>
<term>Optic Atrophy (genetics)</term>
<term>Oxidoreductases Acting on CH-CH Group Donors (chemistry)</term>
<term>Oxidoreductases Acting on CH-CH Group Donors (genetics)</term>
<term>Oxidoreductases Acting on CH-CH Group Donors (metabolism)</term>
<term>Pedigree</term>
<term>RNA Splice Sites (genetics)</term>
<term>Saccharomyces cerevisiae (genetics)</term>
<term>Saccharomyces cerevisiae (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Acides gras (biosynthèse)</term>
<term>Atrophie optique (génétique)</term>
<term>Cellules cultivées</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Fibroblastes</term>
<term>Humains</term>
<term>Maladies mitochondriales (génétique)</term>
<term>Mitochondries (métabolisme)</term>
<term>Modèles moléculaires</term>
<term>Mutation</term>
<term>Mutation faux-sens (génétique)</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Noyaux gris centraux (métabolisme)</term>
<term>Oxidoreductases acting on CH-CH group donors ()</term>
<term>Oxidoreductases acting on CH-CH group donors (génétique)</term>
<term>Oxidoreductases acting on CH-CH group donors (métabolisme)</term>
<term>Pedigree</term>
<term>Saccharomyces cerevisiae (génétique)</term>
<term>Saccharomyces cerevisiae (métabolisme)</term>
<term>Sites d'épissage d'ARN (génétique)</term>
<term>Test de complémentation</term>
<term>Troubles dystoniques (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Fatty Acids</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Oxidoreductases Acting on CH-CH Group Donors</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Acides gras</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Dystonic Disorders</term>
<term>Mitochondrial Diseases</term>
<term>Mutation, Missense</term>
<term>Optic Atrophy</term>
<term>Oxidoreductases Acting on CH-CH Group Donors</term>
<term>RNA Splice Sites</term>
<term>Saccharomyces cerevisiae</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Atrophie optique</term>
<term>Maladies mitochondriales</term>
<term>Mutation faux-sens</term>
<term>Oxidoreductases acting on CH-CH group donors</term>
<term>Saccharomyces cerevisiae</term>
<term>Sites d'épissage d'ARN</term>
<term>Troubles dystoniques</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Basal Ganglia</term>
<term>Mitochondria</term>
<term>Oxidoreductases Acting on CH-CH Group Donors</term>
<term>Saccharomyces cerevisiae</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Mitochondries</term>
<term>Noyaux gris centraux</term>
<term>Oxidoreductases acting on CH-CH group donors</term>
<term>Saccharomyces cerevisiae</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cells, Cultured</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Fibroblasts</term>
<term>Genetic Complementation Test</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Models, Molecular</term>
<term>Mutation</term>
<term>Pedigree</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Cellules cultivées</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Fibroblastes</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Oxidoreductases acting on CH-CH group donors</term>
<term>Pedigree</term>
<term>Test de complémentation</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in <italic>MECR</italic>
 encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285<sup>∗</sup>
), c.247_250del (p.Asn83Hisfs<sup>∗</sup>
4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of <italic>MECR</italic>
. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the <italic>MECR</italic>
 mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in <italic>MECR</italic>
 cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>Finlande</li>
<li>France</li>
<li>Israël</li>
<li>Italie</li>
<li>Tunisie</li>
<li>États-Unis</li>
</country>
<region><li>Gouvernorat de Tunis</li>
<li>Lombardie</li>
<li>Minnesota</li>
<li>Nouvelle-Galles du Sud</li>
<li>Oregon</li>
<li>Victoria (État)</li>
<li>Île-de-France</li>
</region>
<settlement><li>Melbourne</li>
<li>Milan</li>
<li>Paris</li>
<li>Portland</li>
<li>Sydney</li>
<li>Tunis</li>
</settlement>
<orgName><li>Université de Melbourne</li>
<li>Université de Sydney</li>
<li>Université des sciences et de la médecine de l'Oregon</li>
</orgName>
</list>
<tree><country name="Israël"><noRegion><name sortKey="Heimer, Gali" sort="Heimer, Gali" uniqKey="Heimer G" first="Gali" last="Heimer">Gali Heimer</name>
</noRegion>
<name sortKey="Anikster, Yair" sort="Anikster, Yair" uniqKey="Anikster Y" first="Yair" last="Anikster">Yair Anikster</name>
<name sortKey="Anikster, Yair" sort="Anikster, Yair" uniqKey="Anikster Y" first="Yair" last="Anikster">Yair Anikster</name>
<name sortKey="Ben Zeev, Bruria" sort="Ben Zeev, Bruria" uniqKey="Ben Zeev B" first="Bruria" last="Ben-Zeev">Bruria Ben-Zeev</name>
<name sortKey="Ben Zeev, Bruria" sort="Ben Zeev, Bruria" uniqKey="Ben Zeev B" first="Bruria" last="Ben-Zeev">Bruria Ben-Zeev</name>
<name sortKey="Eyal, Eran" sort="Eyal, Eran" uniqKey="Eyal E" first="Eran" last="Eyal">Eran Eyal</name>
<name sortKey="Heimer, Gali" sort="Heimer, Gali" uniqKey="Heimer G" first="Gali" last="Heimer">Gali Heimer</name>
<name sortKey="Heimer, Gali" sort="Heimer, Gali" uniqKey="Heimer G" first="Gali" last="Heimer">Gali Heimer</name>
<name sortKey="Hoffmann, Chen" sort="Hoffmann, Chen" uniqKey="Hoffmann C" first="Chen" last="Hoffmann">Chen Hoffmann</name>
<name sortKey="Marek Yagel, Dina" sort="Marek Yagel, Dina" uniqKey="Marek Yagel D" first="Dina" last="Marek-Yagel">Dina Marek-Yagel</name>
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<name sortKey="Nissenkorn, Andreea" sort="Nissenkorn, Andreea" uniqKey="Nissenkorn A" first="Andreea" last="Nissenkorn">Andreea Nissenkorn</name>
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   |texte=   MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder
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Serveur d'exploration sur les relations entre la France et l'Australie

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

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	Serveur d'exploration sur les relations entre la France et l'Australie
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