Hypermethylation of the CpG Island Near the G4C2 Repeat in ALS with a C9orf72 Expansion
Identifieur interne : 000353 ( Pmc/Corpus ); précédent : 000352; suivant : 000354Hypermethylation of the CpG Island Near the G4C2 Repeat in ALS with a C9orf72 Expansion
Auteurs : Zhengrui Xi ; Lorne Zinman ; Danielle Moreno ; Jennifer Schymick ; Yan Liang ; Christine Sato ; Yonglan Zheng ; Mahdi Ghani ; Samar Dib ; Julia Keith ; Janice Robertson ; Ekaterina RogaevaSource :
- American Journal of Human Genetics [ 0002-9297 ] ; 2013.
Abstract
The G4C2 repeat expansion in
Url:
DOI: 10.1016/j.ajhg.2013.04.017
PubMed: 23731538
PubMed Central: 3675239
Links to Exploration step
PMC:3675239Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hypermethylation of the CpG Island Near the G<sub>4</sub>
C<sub>2</sub>
Repeat in ALS with a <italic>C9orf72</italic>
Expansion</title>
<author><name sortKey="Xi, Zhengrui" sort="Xi, Zhengrui" uniqKey="Xi Z" first="Zhengrui" last="Xi">Zhengrui Xi</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zinman, Lorne" sort="Zinman, Lorne" uniqKey="Zinman L" first="Lorne" last="Zinman">Lorne Zinman</name>
<affiliation><nlm:aff id="aff2">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schymick, Jennifer" sort="Schymick, Jennifer" uniqKey="Schymick J" first="Jennifer" last="Schymick">Jennifer Schymick</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liang, Yan" sort="Liang, Yan" uniqKey="Liang Y" first="Yan" last="Liang">Yan Liang</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zheng, Yonglan" sort="Zheng, Yonglan" uniqKey="Zheng Y" first="Yonglan" last="Zheng">Yonglan Zheng</name>
<affiliation><nlm:aff id="aff3">Department of Medicine, The University of Chicago, Chicago, IL 60637, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dib, Samar" sort="Dib, Samar" uniqKey="Dib S" first="Samar" last="Dib">Samar Dib</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keith, Julia" sort="Keith, Julia" uniqKey="Keith J" first="Julia" last="Keith">Julia Keith</name>
<affiliation><nlm:aff id="aff2">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robertson, Janice" sort="Robertson, Janice" uniqKey="Robertson J" first="Janice" last="Robertson">Janice Robertson</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff4">Department of Medicine, Division of Neurology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hypermethylation of the CpG Island Near the G<sub>4</sub>
C<sub>2</sub>
Repeat in ALS with a <italic>C9orf72</italic>
Expansion</title>
<author><name sortKey="Xi, Zhengrui" sort="Xi, Zhengrui" uniqKey="Xi Z" first="Zhengrui" last="Xi">Zhengrui Xi</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zinman, Lorne" sort="Zinman, Lorne" uniqKey="Zinman L" first="Lorne" last="Zinman">Lorne Zinman</name>
<affiliation><nlm:aff id="aff2">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schymick, Jennifer" sort="Schymick, Jennifer" uniqKey="Schymick J" first="Jennifer" last="Schymick">Jennifer Schymick</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liang, Yan" sort="Liang, Yan" uniqKey="Liang Y" first="Yan" last="Liang">Yan Liang</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zheng, Yonglan" sort="Zheng, Yonglan" uniqKey="Zheng Y" first="Yonglan" last="Zheng">Yonglan Zheng</name>
<affiliation><nlm:aff id="aff3">Department of Medicine, The University of Chicago, Chicago, IL 60637, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dib, Samar" sort="Dib, Samar" uniqKey="Dib S" first="Samar" last="Dib">Samar Dib</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keith, Julia" sort="Keith, Julia" uniqKey="Keith J" first="Julia" last="Keith">Julia Keith</name>
<affiliation><nlm:aff id="aff2">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robertson, Janice" sort="Robertson, Janice" uniqKey="Robertson J" first="Janice" last="Robertson">Janice Robertson</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name>
<affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff4">Department of Medicine, Division of Neurology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff>
</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="2013">2013</date>
</imprint>
</series>
</biblStruct>
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<front><div type="abstract" xml:lang="en"><p>The G<sub>4</sub>
C<sub>2</sub>
repeat expansion in <italic>C9orf72</italic>
is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G<sub>4</sub>
C<sub>2</sub>
repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5′ of the G<sub>4</sub>
C<sub>2</sub>
repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD).</p>
</div>
</front>
</TEI>
<pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id>
<journal-title-group><journal-title>American Journal of Human Genetics</journal-title>
</journal-title-group>
<issn pub-type="ppub">0002-9297</issn>
<issn pub-type="epub">1537-6605</issn>
<publisher><publisher-name>Elsevier</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23731538</article-id>
<article-id pub-id-type="pmc">3675239</article-id>
<article-id pub-id-type="publisher-id">AJHG1419</article-id>
<article-id pub-id-type="doi">10.1016/j.ajhg.2013.04.017</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Report</subject>
</subj-group>
</article-categories>
<title-group><article-title>Hypermethylation of the CpG Island Near the G<sub>4</sub>
C<sub>2</sub>
Repeat in ALS with a <italic>C9orf72</italic>
Expansion</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Xi</surname>
<given-names>Zhengrui</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zinman</surname>
<given-names>Lorne</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Moreno</surname>
<given-names>Danielle</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schymick</surname>
<given-names>Jennifer</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liang</surname>
<given-names>Yan</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sato</surname>
<given-names>Christine</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zheng</surname>
<given-names>Yonglan</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ghani</surname>
<given-names>Mahdi</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dib</surname>
<given-names>Samar</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Keith</surname>
<given-names>Julia</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Robertson</surname>
<given-names>Janice</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rogaeva</surname>
<given-names>Ekaterina</given-names>
</name>
<email>ekaterina.rogaeva@utoronto.ca</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff4" ref-type="aff">4</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada</aff>
<aff id="aff2"><label>2</label>
Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</aff>
<aff id="aff3"><label>3</label>
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA</aff>
<aff id="aff4"><label>4</label>
Department of Medicine, Division of Neurology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>ekaterina.rogaeva@utoronto.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>06</day>
<month>6</month>
<year>2013</year>
</pub-date>
<volume>92</volume>
<issue>6</issue>
<fpage>981</fpage>
<lpage>989</lpage>
<history><date date-type="received"><day>19</day>
<month>3</month>
<year>2013</year>
</date>
<date date-type="rev-recd"><day>5</day>
<month>4</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>22</day>
<month>4</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© 2013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>The American Society of Human Genetics</copyright-holder>
</permissions>
<abstract><p>The G<sub>4</sub>
C<sub>2</sub>
repeat expansion in <italic>C9orf72</italic>
is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G<sub>4</sub>
C<sub>2</sub>
repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5′ of the G<sub>4</sub>
C<sub>2</sub>
repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD).</p>
</abstract>
</article-meta>
</front>
</pmc>
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