Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients
Identifieur interne : 001071 ( Main/Corpus ); précédent : 001070; suivant : 001072Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients
Auteurs : Aleksandar Rakovic ; Anne Grnewald ; Philip Seibler ; Alfredo Ramirez ; Norman Kock ; Slobodanka Orolicki ; Katja Lohmann ; Christine KleinSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-08-15.
Abstract
Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serinethreonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.
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DOI: 10.1093/hmg/ddq215
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Seibler</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kock, Norman" sort="Kock, Norman" uniqKey="Kock N" first="Norman" last="Kock">Norman Kock</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Orolicki, Slobodanka" sort="Orolicki, Slobodanka" uniqKey="Orolicki S" first="Slobodanka" last="Orolicki">Slobodanka Orolicki</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lohmann, Katja" sort="Lohmann, Katja" uniqKey="Lohmann K" first="Katja" last="Lohmann">Katja Lohmann</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>E-mail: christine.klein@neuro.uni-luebeck.de</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:0CB2678AAA06B93248FC3E256D1D0AAA86253AD8</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/hmg/ddq215</idno><idno 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Germany</mods:affiliation></affiliation></author><author><name sortKey="Seibler, Philip" sort="Seibler, Philip" uniqKey="Seibler P" first="Philip" last="Seibler">Philip Seibler</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kock, Norman" sort="Kock, Norman" uniqKey="Kock N" first="Norman" last="Kock">Norman Kock</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Orolicki, Slobodanka" sort="Orolicki, Slobodanka" uniqKey="Orolicki S" first="Slobodanka" last="Orolicki">Slobodanka Orolicki</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lohmann, Katja" sort="Lohmann, Katja" uniqKey="Lohmann K" first="Katja" last="Lohmann">Katja Lohmann</name><affiliation><mods:affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>E-mail: christine.klein@neuro.uni-luebeck.de</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-08-15">2010-08-15</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">16</biblScope><biblScope unit="page" from="3124">3124</biblScope><biblScope unit="page" to="3137">3137</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">0CB2678AAA06B93248FC3E256D1D0AAA86253AD8</idno><idno type="DOI">10.1093/hmg/ddq215</idno><idno type="ArticleID">ddq215</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serinethreonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Aleksandar Rakovic</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Anne Grnewald</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Philip Seibler</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Alfredo Ramirez</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Norman Kock</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Slobodanka Orolicki</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Katja Lohmann</name><affiliations><json:string>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</json:string></affiliations></json:item><json:item><name>Christine Klein</name><affiliations><json:string>E-mail: christine.klein@neuro.uni-luebeck.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>Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serinethreonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. 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Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.</p></abstract></profileDesc><revisionDesc><change when="2010-05-27">Created</change><change when="2010-08-15">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/0CB2678AAA06B93248FC3E256D1D0AAA86253AD8/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/ddq215</article-id><article-id pub-id-type="publisher-id">ddq215</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rakovic</surname><given-names>Aleksandar</given-names></name></contrib><contrib contrib-type="author"><name><surname>Grünewald</surname><given-names>Anne</given-names></name></contrib><contrib contrib-type="author"><name><surname>Seibler</surname><given-names>Philip</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ramirez</surname><given-names>Alfredo</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kock</surname><given-names>Norman</given-names></name></contrib><contrib contrib-type="author"><name><surname>Orolicki</surname><given-names>Slobodanka</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lohmann</surname><given-names>Katja</given-names></name></contrib><contrib contrib-type="author"><name><surname>Klein</surname><given-names>Christine</given-names></name><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff><addr-line>Section of Clinical and Molecular Neurogenetics, Department of Neurology</addr-line>, <institution>University of Lübeck</institution>, <addr-line>23562 Lübeck</addr-line>, <country>Germany</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Section of Clinical and Molecular Neurogenetics, Department of Neurology</addr-line>, <institution>University of Lübeck</institution>, <addr-line>Ratzeburger Allee 160, 23538, Lübeck</addr-line>, <country>Germany.</country> Tel: <phone>+49 4512903353</phone>; Fax: <fax>+49 4512903355</fax>; Email: <email>christine.klein@neuro.uni-luebeck.de</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>8</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>27</day><month>5</month><year>2010</year></pub-date><volume>19</volume><issue>16</issue><fpage>3124</fpage><lpage>3137</lpage><history><date date-type="received"><day>13</day><month>4</month><year>2010</year></date><date date-type="accepted"><day>21</day><month>5</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><abstract><p>Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine–threonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients</title></titleInfo><name type="personal"><namePart type="given">Aleksandar</namePart><namePart type="family">Rakovic</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Grnewald</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philip</namePart><namePart type="family">Seibler</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alfredo</namePart><namePart type="family">Ramirez</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Norman</namePart><namePart type="family">Kock</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Slobodanka</namePart><namePart type="family">Orolicki</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katja</namePart><namePart type="family">Lohmann</namePart><affiliation>Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lbeck, 23562 Lbeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine</namePart><namePart type="family">Klein</namePart><affiliation>E-mail: christine.klein@neuro.uni-luebeck.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">2010-08-15</dateIssued><dateCreated encoding="w3cdtf">2010-05-27</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>Mutations in the PTEN-induced putative kinase 1 (PINK1), a mitochondrial serinethreonine kinase, and Parkin, an E3 ubiquitin ligase, are associated with autosomal-recessive forms of Parkinson disease (PD). Both are involved in the maintenance of mitochondrial integrity and protection from multiple stressors. Recently, Parkin was demonstrated to be recruited to impaired mitochondria in a PINK1-dependent manner, where it triggers mitophagy. Using primary human dermal fibroblasts originating from PD patients with various PINK1 mutations, we showed at the endogenous level that (i) PINK1 regulates the stress-induced decrease of endogenous Parkin; (ii) mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of Parkin; (iii) endogenous PINK1 is stabilized on depolarized mitochondria; and (iv) mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin signal and its mitochondrial translocation. Furthermore, we showed that different stressors, depolarizing or non-depolarizing, led to the same effect on detectable Parkin levels and its mitochondrial targeting. Although this effect on Parkin was independent of the mitochondrial membrane potential, we demonstrate a differential effect of depolarizing versus non-depolarizing stressors on endogenous levels of PINK1. Our study shows the necessity to introduce an environmental factor, i.e. stress, to visualize the differences in the interaction of PINK1 and Parkin in mutants versus controls. Establishing human fibroblasts as a suitable model for studying this interaction, we extend data from animal and other cellular models and provide experimental evidence for the generally held notion of PD as a condition with a combined genetic and environmental etiology.</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>16</number></detail><extent unit="pages"><start>3124</start><end>3137</end></extent></part></relatedItem><identifier type="istex">0CB2678AAA06B93248FC3E256D1D0AAA86253AD8</identifier><identifier type="DOI">10.1093/hmg/ddq215</identifier><identifier type="ArticleID">ddq215</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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