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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Jump from Pre-mutation to Pathologic Expansion in <italic>C9orf72</italic></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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Van Blitterswijk, Marka" sort="Van Blitterswijk, Marka" uniqKey="Van Blitterswijk M" first="Marka" last="Van Blitterswijk">Marka Van Blitterswijk</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Ming" sort="Zhang, Ming" uniqKey="Zhang M" first="Ming" last="Zhang">Ming Zhang</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mcgoldrick, Philip" sort="Mcgoldrick, Philip" uniqKey="Mcgoldrick P" first="Philip" last="Mcgoldrick">Philip Mcgoldrick</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mclean, Jesse R" sort="Mclean, Jesse R" uniqKey="Mclean J" first="Jesse R." last="Mclean">Jesse R. Mclean</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Yunusova, Yana" sort="Yunusova, Yana" uniqKey="Yunusova Y" first="Yana" last="Yunusova">Yana Yunusova</name><affiliation><nlm:aff id="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Speech Language Pathology, University of Toronto, 500 University Avenue, Toronto, ON M5G 1V7, Canada</nlm:aff></affiliation></author><author><name sortKey="Knock, Erin" sort="Knock, Erin" uniqKey="Knock E" first="Erin" last="Knock">Erin Knock</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mckeever, Paul M" sort="Mckeever, Paul M" uniqKey="Mckeever P" first="Paul M." last="Mckeever">Paul M. Mckeever</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, Canada</nlm:aff></affiliation></author><author><name sortKey="Schneider, Raphael" sort="Schneider, Raphael" uniqKey="Schneider R" first="Raphael" last="Schneider">Raphael Schneider</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, 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="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation></author><author><name sortKey="Petrescu, Nicolae" sort="Petrescu, Nicolae" uniqKey="Petrescu N" first="Nicolae" last="Petrescu">Nicolae Petrescu</name><affiliation><nlm:aff id="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff></affiliation></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Tartaglia, Maria Carmela" sort="Tartaglia, Maria Carmela" uniqKey="Tartaglia M" first="Maria Carmela" last="Tartaglia">Maria Carmela Tartaglia</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff></affiliation></author><author><name sortKey="Baker, Matthew C" sort="Baker, Matthew C" uniqKey="Baker M" first="Matthew C." last="Baker">Matthew C. Baker</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff7">Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Boylan, Kevin B" sort="Boylan, Kevin B" uniqKey="Boylan K" first="Kevin B." last="Boylan">Kevin B. Boylan</name><affiliation><nlm:aff id="aff7">Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis W" sort="Dickson, Dennis W" uniqKey="Dickson D" first="Dennis W." last="Dickson">Dennis W. Dickson</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation><nlm:aff id="aff8">Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 West Mall, Vancouver, BC V6T 1Z4, Canada</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, 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="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26004200</idno><idno type="pmc">4457950</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457950</idno><idno type="RBID">PMC:4457950</idno><idno type="doi">10.1016/j.ajhg.2015.04.016</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000355</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000355</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Jump from Pre-mutation to Pathologic Expansion in <italic>C9orf72</italic></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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Van Blitterswijk, Marka" sort="Van Blitterswijk, Marka" uniqKey="Van Blitterswijk M" first="Marka" last="Van Blitterswijk">Marka Van Blitterswijk</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Ming" sort="Zhang, Ming" uniqKey="Zhang M" first="Ming" last="Zhang">Ming Zhang</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mcgoldrick, Philip" sort="Mcgoldrick, Philip" uniqKey="Mcgoldrick P" first="Philip" last="Mcgoldrick">Philip Mcgoldrick</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mclean, Jesse R" sort="Mclean, Jesse R" uniqKey="Mclean J" first="Jesse R." last="Mclean">Jesse R. Mclean</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Yunusova, Yana" sort="Yunusova, Yana" uniqKey="Yunusova Y" first="Yana" last="Yunusova">Yana Yunusova</name><affiliation><nlm:aff id="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Speech Language Pathology, University of Toronto, 500 University Avenue, Toronto, ON M5G 1V7, Canada</nlm:aff></affiliation></author><author><name sortKey="Knock, Erin" sort="Knock, Erin" uniqKey="Knock E" first="Erin" last="Knock">Erin Knock</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Mckeever, Paul M" sort="Mckeever, Paul M" uniqKey="Mckeever P" first="Paul M." last="Mckeever">Paul M. Mckeever</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, Canada</nlm:aff></affiliation></author><author><name sortKey="Schneider, Raphael" sort="Schneider, Raphael" uniqKey="Schneider R" first="Raphael" last="Schneider">Raphael Schneider</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, 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="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation></author><author><name sortKey="Petrescu, Nicolae" sort="Petrescu, Nicolae" uniqKey="Petrescu N" first="Nicolae" last="Petrescu">Nicolae Petrescu</name><affiliation><nlm:aff id="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff></affiliation></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation></author><author><name sortKey="Tartaglia, Maria Carmela" sort="Tartaglia, Maria Carmela" uniqKey="Tartaglia M" first="Maria Carmela" last="Tartaglia">Maria Carmela Tartaglia</name><affiliation><nlm:aff id="aff1">Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</nlm:aff></affiliation></author><author><name sortKey="Baker, Matthew C" sort="Baker, Matthew C" uniqKey="Baker M" first="Matthew C." last="Baker">Matthew C. Baker</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff7">Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Boylan, Kevin B" sort="Boylan, Kevin B" uniqKey="Boylan K" first="Kevin B." last="Boylan">Kevin B. Boylan</name><affiliation><nlm:aff id="aff7">Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis W" sort="Dickson, Dennis W" uniqKey="Dickson D" first="Dennis W." last="Dickson">Dennis W. Dickson</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</nlm:aff></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation><nlm:aff id="aff8">Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 West Mall, Vancouver, BC V6T 1Z4, Canada</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="aff2">Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, 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="aff3">Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, 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, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Division of Neurology, Department of Medicine, 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="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>An expanded G<sub>4</sub>C<sub>2</sub> repeat in <italic>C9orf72</italic> represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring’s large expansions (which were methylated and associated with reduced <italic>C9orf72</italic> expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of <italic>C9orf72</italic>). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered “pre-mutations” to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).</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">26004200</article-id><article-id pub-id-type="pmc">4457950</article-id><article-id pub-id-type="publisher-id">S0002-9297(15)00153-6</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2015.04.016</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Jump from Pre-mutation to Pathologic Expansion in <italic>C9orf72</italic></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><xref rid="fn1" ref-type="fn">9</xref></contrib><contrib contrib-type="author"><name><surname>van Blitterswijk</surname><given-names>Marka</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">9</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Ming</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">9</xref></contrib><contrib contrib-type="author"><name><surname>McGoldrick</surname><given-names>Philip</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>McLean</surname><given-names>Jesse R.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Yunusova</surname><given-names>Yana</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Knock</surname><given-names>Erin</given-names></name><xref rid="aff1" ref-type="aff">1</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>Sato</surname><given-names>Christine</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>McKeever</surname><given-names>Paul M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Raphael</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Keith</surname><given-names>Julia</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Petrescu</surname><given-names>Nicolae</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Fraser</surname><given-names>Paul</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Tartaglia</surname><given-names>Maria Carmela</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Baker</surname><given-names>Matthew C.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Graff-Radford</surname><given-names>Neill R.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Boylan</surname><given-names>Kevin B.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Dickson</surname><given-names>Dennis W.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Mackenzie</surname><given-names>Ian R.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Rademakers</surname><given-names>Rosa</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><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Zinman</surname><given-names>Lorne</given-names></name><email>lorne.zinman@sunnybrook.ca</email><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff6" ref-type="aff">6</xref><xref rid="cor1" ref-type="corresp">∗</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="aff6" ref-type="aff">6</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada</aff><aff id="aff2"><label>2</label>Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</aff><aff id="aff3"><label>3</label>Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada</aff><aff id="aff4"><label>4</label>Department of Speech Language Pathology, University of Toronto, 500 University Avenue, Toronto, ON M5G 1V7, Canada</aff><aff id="aff5"><label>5</label>Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1, Canada</aff><aff id="aff6"><label>6</label>Division of Neurology, Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada</aff><aff id="aff7"><label>7</label>Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA</aff><aff id="aff8"><label>8</label>Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 West Mall, Vancouver, BC V6T 1Z4, Canada</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>lorne.zinman@sunnybrook.ca</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>ekaterina.rogaeva@utoronto.ca</email></corresp><fn id="fn1"><label>9</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>04</day><month>6</month><year>2015</year></pub-date><volume>96</volume><issue>6</issue><fpage>962</fpage><lpage>970</lpage><history><date date-type="received"><day>12</day><month>3</month><year>2015</year></date><date date-type="accepted"><day>22</day><month>4</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>An expanded G<sub>4</sub>C<sub>2</sub> repeat in <italic>C9orf72</italic> represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring’s large expansions (which were methylated and associated with reduced <italic>C9orf72</italic> expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of <italic>C9orf72</italic>). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered “pre-mutations” to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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