Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis
Identifieur interne : 000E58 ( Main/Corpus ); précédent : 000E57; suivant : 000E59Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis
Auteurs : Lena F. Burbulla ; Carina Schelling ; Hiroki Kato ; Doron Rapaport ; Dirk Woitalla ; Carola Schiesling ; Claudia Schulte ; Manu Sharma ; Thomas Illig ; Peter Bauer ; Stephan Jung ; Alfred Nordheim ; Ludger Schls ; Olaf Riess ; Rejko KrgerSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-11-15.
Abstract
The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.
Url:
DOI: 10.1093/hmg/ddq370
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Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Lena F. Burbulla</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string><json:string>Graduate School of Cellular & Molecular Neuroscience,</json:string></affiliations></json:item><json:item><name>Carina Schelling</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string></affiliations></json:item><json:item><name>Hiroki Kato</name><affiliations><json:string>Interfaculty Institute for Biochemistry,</json:string></affiliations></json:item><json:item><name>Doron Rapaport</name><affiliations><json:string>Interfaculty Institute for Biochemistry,</json:string></affiliations></json:item><json:item><name>Dirk Woitalla</name><affiliations><json:string>Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany and</json:string></affiliations></json:item><json:item><name>Carola Schiesling</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string></affiliations></json:item><json:item><name>Claudia Schulte</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string></affiliations></json:item><json:item><name>Manu Sharma</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string></affiliations></json:item><json:item><name>Thomas Illig</name><affiliations><json:string>Institute of Epidemiology, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Peter Bauer</name><affiliations><json:string>Medical Genetics and</json:string></affiliations></json:item><json:item><name>Stephan Jung</name><affiliations><json:string>Proteome Center Tbingen, Interfaculty Institute for Cell Biology, University of Tbingen, Tbingen, Germany and</json:string></affiliations></json:item><json:item><name>Alfred Nordheim</name><affiliations><json:string>Proteome Center Tbingen, Interfaculty Institute for Cell Biology, University of Tbingen, Tbingen, Germany and</json:string></affiliations></json:item><json:item><name>Ludger Schls</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string></affiliations></json:item><json:item><name>Olaf Riess</name><affiliations><json:string>Medical Genetics and</json:string></affiliations></json:item><json:item><name>Rejko Krger</name><affiliations><json:string>DZNE, German Center for Neurodegenerative Diseases, Tbingen, Germany,</json:string><json:string>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research,</json:string><json:string>E-mail: rejko.krueger@uni-tuebingen.de</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><abstract>The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.</abstract><qualityIndicators><score>8.988</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1750</abstractCharCount><pdfWordCount>10114</pdfWordCount><pdfCharCount>64399</pdfCharCount><pdfPageCount>16</pdfPageCount><abstractWordCount>249</abstractWordCount></qualityIndicators><title>Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial 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Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.</p></abstract></profileDesc><revisionDesc><change when="2010-09-02">Created</change><change when="2010-11-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/5C30630DF1DE51930BD486321A5168E80D9459A6/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddq370</article-id><article-id pub-id-type="publisher-id">ddq370</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Burbulla</surname><given-names>Lena F.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Schelling</surname><given-names>Carina</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kato</surname><given-names>Hiroki</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Rapaport</surname><given-names>Doron</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Woitalla</surname><given-names>Dirk</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Schiesling</surname><given-names>Carola</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Schulte</surname><given-names>Claudia</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sharma</surname><given-names>Manu</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Illig</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Bauer</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Stephan</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Nordheim</surname><given-names>Alfred</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Schöls</surname><given-names>Ludger</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Riess</surname><given-names>Olaf</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Krüger</surname><given-names>Rejko</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany</addr-line>,</aff><aff id="af2"><label>2</label><addr-line>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research</addr-line>,</aff><aff id="af3"><label>3</label><addr-line>Graduate School of Cellular & Molecular Neuroscience</addr-line>,</aff><aff id="af4"><label>4</label><addr-line>Interfaculty Institute for Biochemistry</addr-line>,</aff><aff id="af5"><label>5</label><addr-line>Medical Genetics</addr-line> and</aff><aff id="af6"><label>6</label><addr-line>Proteome Center Tübingen, Interfaculty Institute for Cell Biology</addr-line>, <institution>University of Tübingen</institution>, <addr-line>Tübingen</addr-line>, <country>Germany</country> and</aff><aff id="af7"><label>7</label><addr-line>Department of Neurology</addr-line>, <institution>St Josef-Hospital, Ruhr-University Bochum</institution>, <addr-line>Bochum</addr-line>, <country>Germany</country> and</aff><aff id="af8"><label>8</label><addr-line>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Envir</addr-line><addr-line>onmental Health, Neuherberg</addr-line>, <country>Germany</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: Laboratory of Functional Neurogenomics, Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. Tel: +49 70712982141; Fax: +49 7071295260; Email: <email>rejko.krueger@uni-tuebingen.de</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>2</day><month>9</month><year>2010</year></pub-date><volume>19</volume><issue>22</issue><fpage>4437</fpage><lpage>4452</lpage><history><date date-type="received"><day>21</day><month>7</month><year>2010</year></date><date date-type="rev-recd"><day>20</day><month>8</month><year>2010</year></date><date date-type="accepted"><day>26</day><month>8</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2010</copyright-year></permissions><self-uri content-type="pdf" xlink:href="ddq370.pdf"></self-uri><abstract><p>The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. <italic>In vitro</italic> import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the <italic>mortalin</italic> gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis</title></titleInfo><name type="personal"><namePart type="given">Lena F.</namePart><namePart type="family">Burbulla</namePart><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carina</namePart><namePart type="family">Schelling</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hiroki</namePart><namePart type="family">Kato</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Doron</namePart><namePart type="family">Rapaport</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dirk</namePart><namePart type="family">Woitalla</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carola</namePart><namePart type="family">Schiesling</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Claudia</namePart><namePart type="family">Schulte</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Manu</namePart><namePart type="family">Sharma</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Illig</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Bauer</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephan</namePart><namePart type="family">Jung</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alfred</namePart><namePart type="family">Nordheim</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ludger</namePart><namePart type="family">Schls</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Olaf</namePart><namePart type="family">Riess</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rejko</namePart><namePart type="family">Krger</namePart><affiliation></affiliation><affiliation></affiliation><affiliation>E-mail: rejko.krueger@uni-tuebingen.de</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-11-15</dateIssued><dateCreated encoding="w3cdtf">2010-09-02</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>22</number></detail><extent unit="pages"><start>4437</start><end>4452</end></extent></part></relatedItem><identifier type="istex">5C30630DF1DE51930BD486321A5168E80D9459A6</identifier><identifier type="DOI">10.1093/hmg/ddq370</identifier><identifier type="href">ddq370.pdf</identifier><identifier type="ArticleID">ddq370</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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