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The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype
MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early chil...
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| Published in: | Brain (London, England : 1878) England : 1878), 2012-01, Vol.135 (1), p.23-34 |
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| container_end_page | 34 |
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| container_title | Brain (London, England : 1878) |
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| creator | Rouzier, Cécile Bannwarth, Sylvie Chaussenot, Annabelle Chevrollier, Arnaud Verschueren, Annie Bonello-Palot, Nathalie Fragaki, Konstantina Cano, Aline Pouget, Jean Pellissier, Jean-François Procaccio, Vincent Chabrol, Brigitte Paquis-Flucklinger, Véronique |
| description | MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. |
| doi_str_mv | 10.1093/brain/awr323 |
| format | article |
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They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability.</description><identifier>ISSN: 0006-8950</identifier><identifier>EISSN: 1460-2156</identifier><identifier>DOI: 10.1093/brain/awr323</identifier><identifier>PMID: 22189565</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adolescent ; Adult ; Biological and medical sciences ; Charcot-Marie-Tooth disease ; Child ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; DNA Damage ; DNA, Mitochondrial - genetics ; DNA, Mitochondrial - metabolism ; Female ; GTP Phosphohydrolases - genetics ; GTP Phosphohydrolases - metabolism ; Humans ; Life Sciences ; Male ; Medical sciences ; Middle Aged ; Mitochondrial Myopathies - complications ; Mitochondrial Myopathies - genetics ; Mitochondrial Myopathies - metabolism ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Mutation, Missense ; Neurology ; Optic Atrophy - complications ; Optic Atrophy - genetics ; Optic Atrophy - metabolism ; Pedigree</subject><ispartof>Brain (London, England : 1878), 2012-01, Vol.135 (1), p.23-34</ispartof><rights>The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2011</rights><rights>2015 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-21c5f6138c9fbc101e0718c1ba025cd79457d2e624629c07353f63024b6155583</citedby><cites>FETCH-LOGICAL-c523t-21c5f6138c9fbc101e0718c1ba025cd79457d2e624629c07353f63024b6155583</cites><orcidid>0000-0002-5135-6643</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,1591,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25544319$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22189565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-angers.hal.science/hal-03408506$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Rouzier, Cécile</creatorcontrib><creatorcontrib>Bannwarth, Sylvie</creatorcontrib><creatorcontrib>Chaussenot, Annabelle</creatorcontrib><creatorcontrib>Chevrollier, Arnaud</creatorcontrib><creatorcontrib>Verschueren, Annie</creatorcontrib><creatorcontrib>Bonello-Palot, Nathalie</creatorcontrib><creatorcontrib>Fragaki, Konstantina</creatorcontrib><creatorcontrib>Cano, Aline</creatorcontrib><creatorcontrib>Pouget, Jean</creatorcontrib><creatorcontrib>Pellissier, Jean-François</creatorcontrib><creatorcontrib>Procaccio, Vincent</creatorcontrib><creatorcontrib>Chabrol, Brigitte</creatorcontrib><creatorcontrib>Paquis-Flucklinger, Véronique</creatorcontrib><title>The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype</title><title>Brain (London, England : 1878)</title><addtitle>Brain</addtitle><description>MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Charcot-Marie-Tooth disease</subject><subject>Child</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>DNA Damage</subject><subject>DNA, Mitochondrial - genetics</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Female</subject><subject>GTP Phosphohydrolases - genetics</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mitochondrial Myopathies - complications</subject><subject>Mitochondrial Myopathies - genetics</subject><subject>Mitochondrial Myopathies - metabolism</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Mutation, Missense</subject><subject>Neurology</subject><subject>Optic Atrophy - complications</subject><subject>Optic Atrophy - genetics</subject><subject>Optic Atrophy - metabolism</subject><subject>Pedigree</subject><issn>0006-8950</issn><issn>1460-2156</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNp90U1v1DAQBmALUdGlcOOMfEELUpeOP5McV6UfSEu5lLPlOA4x8trBTor239ftLu2tJ0ujRzPjeRH6QOArgYadtUm7cKb_JUbZK7QgXMKKEiFfowUAyFXdCDhGb3P-A0A4o_INOqaUlLIUC6RvB4t_XN5Q_NsGi13GyeYxhuxab3EfE966KZohhi457fG3mzV2IU-6dd5NO6xDh-M4OYP1lOI47PBy9HNe4nGwIU670b5DR7322b4_vCfo1-XF7fn1avPz6vv5erMygrKprGxELwmrTdO3hgCxUJHakFYDFaarGi6qjlpJuaSNgYoJ1ksGlLeSCCFqdoK-7PsO2qsxua1OOxW1U9frjXqoAeNQC5B3pNjl3o4p_p1tntTWZWO918HGOaumnIdRkKLIzy_KclEOtGLACz3dU5Nizsn2T1sQUA9Rqceo1D6qwj8eOs_t1nZP-H82BXw6AJ2N9n3Swbj87ITgnJHm-TNxHl8eeQ_AUqgS</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Rouzier, Cécile</creator><creator>Bannwarth, Sylvie</creator><creator>Chaussenot, Annabelle</creator><creator>Chevrollier, Arnaud</creator><creator>Verschueren, Annie</creator><creator>Bonello-Palot, Nathalie</creator><creator>Fragaki, Konstantina</creator><creator>Cano, Aline</creator><creator>Pouget, Jean</creator><creator>Pellissier, Jean-François</creator><creator>Procaccio, Vincent</creator><creator>Chabrol, Brigitte</creator><creator>Paquis-Flucklinger, Véronique</creator><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-5135-6643</orcidid></search><sort><creationdate>20120101</creationdate><title>The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype</title><author>Rouzier, Cécile ; Bannwarth, Sylvie ; Chaussenot, Annabelle ; Chevrollier, Arnaud ; Verschueren, Annie ; Bonello-Palot, Nathalie ; Fragaki, Konstantina ; Cano, Aline ; Pouget, Jean ; Pellissier, Jean-François ; Procaccio, Vincent ; Chabrol, Brigitte ; Paquis-Flucklinger, Véronique</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-21c5f6138c9fbc101e0718c1ba025cd79457d2e624629c07353f63024b6155583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Charcot-Marie-Tooth disease</topic><topic>Child</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>DNA Damage</topic><topic>DNA, Mitochondrial - genetics</topic><topic>DNA, Mitochondrial - metabolism</topic><topic>Female</topic><topic>GTP Phosphohydrolases - genetics</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mitochondrial Myopathies - complications</topic><topic>Mitochondrial Myopathies - genetics</topic><topic>Mitochondrial Myopathies - metabolism</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>Mutation, Missense</topic><topic>Neurology</topic><topic>Optic Atrophy - complications</topic><topic>Optic Atrophy - genetics</topic><topic>Optic Atrophy - metabolism</topic><topic>Pedigree</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rouzier, Cécile</creatorcontrib><creatorcontrib>Bannwarth, Sylvie</creatorcontrib><creatorcontrib>Chaussenot, Annabelle</creatorcontrib><creatorcontrib>Chevrollier, Arnaud</creatorcontrib><creatorcontrib>Verschueren, Annie</creatorcontrib><creatorcontrib>Bonello-Palot, Nathalie</creatorcontrib><creatorcontrib>Fragaki, Konstantina</creatorcontrib><creatorcontrib>Cano, Aline</creatorcontrib><creatorcontrib>Pouget, Jean</creatorcontrib><creatorcontrib>Pellissier, Jean-François</creatorcontrib><creatorcontrib>Procaccio, Vincent</creatorcontrib><creatorcontrib>Chabrol, Brigitte</creatorcontrib><creatorcontrib>Paquis-Flucklinger, Véronique</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Brain (London, England : 1878)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rouzier, Cécile</au><au>Bannwarth, Sylvie</au><au>Chaussenot, Annabelle</au><au>Chevrollier, Arnaud</au><au>Verschueren, Annie</au><au>Bonello-Palot, Nathalie</au><au>Fragaki, Konstantina</au><au>Cano, Aline</au><au>Pouget, Jean</au><au>Pellissier, Jean-François</au><au>Procaccio, Vincent</au><au>Chabrol, Brigitte</au><au>Paquis-Flucklinger, Véronique</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype</atitle><jtitle>Brain (London, England : 1878)</jtitle><addtitle>Brain</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>135</volume><issue>1</issue><spage>23</spage><epage>34</epage><pages>23-34</pages><issn>0006-8950</issn><eissn>1460-2156</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><abstract>MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>22189565</pmid><doi>10.1093/brain/awr323</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-5135-6643</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Brain (London, England : 1878), 2012-01, Vol.135 (1), p.23-34 |
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| source | Oxford Academic Journals (OUP) |
| subjects | Adolescent Adult Biological and medical sciences Charcot-Marie-Tooth disease Child Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DNA Damage DNA, Mitochondrial - genetics DNA, Mitochondrial - metabolism Female GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism Humans Life Sciences Male Medical sciences Middle Aged Mitochondrial Myopathies - complications Mitochondrial Myopathies - genetics Mitochondrial Myopathies - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Mutation, Missense Neurology Optic Atrophy - complications Optic Atrophy - genetics Optic Atrophy - metabolism Pedigree |
| title | The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype |
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