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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>TMEM106B</italic> is a genetic modifier of frontotemporal lobar degeneration with <italic>C9orf72</italic> hexanucleotide repeat expansions</title><author><name sortKey="Gallagher, Michael D" sort="Gallagher, Michael D" uniqKey="Gallagher M" first="Michael D." last="Gallagher">Michael D. Gallagher</name><affiliation><nlm:aff id="A1">Cell & Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Suh, Eunran" sort="Suh, Eunran" uniqKey="Suh E" first="Eunran" last="Suh">Eunran Suh</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Grossman, Murray" sort="Grossman, Murray" uniqKey="Grossman M" first="Murray" last="Grossman">Murray Grossman</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Elman, Lauren" sort="Elman, Lauren" uniqKey="Elman L" first="Lauren" last="Elman">Lauren Elman</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Mccluskey, Leo" sort="Mccluskey, Leo" uniqKey="Mccluskey L" first="Leo" last="Mccluskey">Leo Mccluskey</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Van Swieten, John C" sort="Van Swieten, John C" uniqKey="Van Swieten J" first="John C." last="Van Swieten">John C. Van Swieten</name><affiliation><nlm:aff id="A4">Erasmus Medical Centre, s’Gravendijkwal 230, Rotterdam</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Alzheimercenter Vumc, Boelelaan 1118, Amsterdam</nlm:aff></affiliation></author><author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name><affiliation><nlm:aff id="A6">King’s College Hospital, London</nlm:aff></affiliation></author><author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name><affiliation><nlm:aff id="A7">University of Tübingen, Calwerstr. 3, 72072 Tübingen, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A8">German Center for Neurodegenerative Diseases (DZNE)</nlm:aff></affiliation></author><author><name sortKey="Gelpi, Ellen" sort="Gelpi, Ellen" uniqKey="Gelpi E" first="Ellen" last="Gelpi">Ellen Gelpi</name><affiliation><nlm:aff id="A9">Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de Medicina, c/Casanova 143, planta 0, ala sur. 08036 Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name><affiliation><nlm:aff id="A10">Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN</nlm:aff></affiliation></author><author><name sortKey="Rohrer, Jonathan D" sort="Rohrer, Jonathan D" uniqKey="Rohrer J" first="Jonathan D." last="Rohrer">Jonathan D. Rohrer</name><affiliation><nlm:aff id="A11">Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Halliday, Glenda" sort="Halliday, Glenda" uniqKey="Halliday G" first="Glenda" last="Halliday">Glenda Halliday</name><affiliation><nlm:aff id="A12">Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A13">Faculty of Medicine, University of New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><nlm:aff id="A14">Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerpen, Belgium</nlm:aff></affiliation></author><author><name sortKey="Seilhean, Danielle" sort="Seilhean, Danielle" uniqKey="Seilhean D" first="Danielle" last="Seilhean">Danielle Seilhean</name><affiliation><nlm:aff id="A15">University Pierre et Marie Curie (UPMC)-Sorbonne University, France</nlm:aff></affiliation></author><author><name sortKey="Shaw, Pamela J" sort="Shaw, Pamela J" uniqKey="Shaw P" first="Pamela J." last="Shaw">Pamela J. Shaw</name><affiliation><nlm:aff id="A16">University of Sheffield, UK</nlm:aff></affiliation></author><author><name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P." last="Frosch">Matthew P. Frosch</name><affiliation><nlm:aff id="A17">Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Lee, Virginia M Y" sort="Lee, Virginia M Y" uniqKey="Lee V" first="Virginia M. Y." last="Lee">Virginia M. Y. Lee</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Van Deerlin, Vivianna" sort="Van Deerlin, Vivianna" uniqKey="Van Deerlin V" first="Vivianna" last="Van Deerlin">Vivianna Van Deerlin</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Chen Plotkin, Alice S" sort="Chen Plotkin, Alice S" uniqKey="Chen Plotkin A" first="Alice S." last="Chen-Plotkin">Alice S. Chen-Plotkin</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24442578</idno><idno type="pmc">4003885</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003885</idno><idno type="RBID">PMC:4003885</idno><idno type="doi">10.1007/s00401-013-1239-x</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001D42</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001D42</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>TMEM106B</italic> is a genetic modifier of frontotemporal lobar degeneration with <italic>C9orf72</italic> hexanucleotide repeat expansions</title><author><name sortKey="Gallagher, Michael D" sort="Gallagher, Michael D" uniqKey="Gallagher M" first="Michael D." last="Gallagher">Michael D. Gallagher</name><affiliation><nlm:aff id="A1">Cell & Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Suh, Eunran" sort="Suh, Eunran" uniqKey="Suh E" first="Eunran" last="Suh">Eunran Suh</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Grossman, Murray" sort="Grossman, Murray" uniqKey="Grossman M" first="Murray" last="Grossman">Murray Grossman</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Elman, Lauren" sort="Elman, Lauren" uniqKey="Elman L" first="Lauren" last="Elman">Lauren Elman</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Mccluskey, Leo" sort="Mccluskey, Leo" uniqKey="Mccluskey L" first="Leo" last="Mccluskey">Leo Mccluskey</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Van Swieten, John C" sort="Van Swieten, John C" uniqKey="Van Swieten J" first="John C." last="Van Swieten">John C. Van Swieten</name><affiliation><nlm:aff id="A4">Erasmus Medical Centre, s’Gravendijkwal 230, Rotterdam</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Alzheimercenter Vumc, Boelelaan 1118, Amsterdam</nlm:aff></affiliation></author><author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name><affiliation><nlm:aff id="A6">King’s College Hospital, London</nlm:aff></affiliation></author><author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name><affiliation><nlm:aff id="A7">University of Tübingen, Calwerstr. 3, 72072 Tübingen, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A8">German Center for Neurodegenerative Diseases (DZNE)</nlm:aff></affiliation></author><author><name sortKey="Gelpi, Ellen" sort="Gelpi, Ellen" uniqKey="Gelpi E" first="Ellen" last="Gelpi">Ellen Gelpi</name><affiliation><nlm:aff id="A9">Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de Medicina, c/Casanova 143, planta 0, ala sur. 08036 Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name><affiliation><nlm:aff id="A10">Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN</nlm:aff></affiliation></author><author><name sortKey="Rohrer, Jonathan D" sort="Rohrer, Jonathan D" uniqKey="Rohrer J" first="Jonathan D." last="Rohrer">Jonathan D. Rohrer</name><affiliation><nlm:aff id="A11">Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Halliday, Glenda" sort="Halliday, Glenda" uniqKey="Halliday G" first="Glenda" last="Halliday">Glenda Halliday</name><affiliation><nlm:aff id="A12">Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A13">Faculty of Medicine, University of New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><nlm:aff id="A14">Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerpen, Belgium</nlm:aff></affiliation></author><author><name sortKey="Seilhean, Danielle" sort="Seilhean, Danielle" uniqKey="Seilhean D" first="Danielle" last="Seilhean">Danielle Seilhean</name><affiliation><nlm:aff id="A15">University Pierre et Marie Curie (UPMC)-Sorbonne University, France</nlm:aff></affiliation></author><author><name sortKey="Shaw, Pamela J" sort="Shaw, Pamela J" uniqKey="Shaw P" first="Pamela J." last="Shaw">Pamela J. Shaw</name><affiliation><nlm:aff id="A16">University of Sheffield, UK</nlm:aff></affiliation></author><author><name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P." last="Frosch">Matthew P. Frosch</name><affiliation><nlm:aff id="A17">Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Lee, Virginia M Y" sort="Lee, Virginia M Y" uniqKey="Lee V" first="Virginia M. Y." last="Lee">Virginia M. Y. Lee</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Van Deerlin, Vivianna" sort="Van Deerlin, Vivianna" uniqKey="Van Deerlin V" first="Vivianna" last="Van Deerlin">Vivianna Van Deerlin</name><affiliation><nlm:aff id="A3">Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author><author><name sortKey="Chen Plotkin, Alice S" sort="Chen Plotkin, Alice S" uniqKey="Chen Plotkin A" first="Alice S." last="Chen-Plotkin">Alice S. Chen-Plotkin</name><affiliation><nlm:aff id="A2">Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</nlm:aff></affiliation></author></analytic><series><title level="j">Acta neuropathologica</title><idno type="ISSN">0001-6322</idno><idno type="eISSN">1432-0533</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (<italic>C9orf72)</italic> have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at <italic>TMEM106B</italic> influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP). Previous reports have shown that <italic>TMEM106B</italic> is a genetic modifier of FTLD-TDP caused by progranulin (<italic>GRN</italic>) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with <italic>C9orf72</italic> expansions (n=14), with the major allele correlated with later age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with <italic>C9orf72</italic> expansions (n=75), again finding that the major allele associates with later age at death (p=0.016), as well as later age at onset (p=0.019). In contrast, <italic>TMEM106B</italic> genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for <italic>GRN</italic> mutations or <italic>C9orf72</italic> expansions. Thus, <italic>TMEM106B</italic> is a genetic modifier of FTLD with <italic>C9orf72</italic> expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in <italic>C9orf72</italic> expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0412041</journal-id><journal-id journal-id-type="pubmed-jr-id">133</journal-id><journal-id journal-id-type="nlm-ta">Acta Neuropathol</journal-id><journal-id journal-id-type="iso-abbrev">Acta Neuropathol.</journal-id><journal-title-group><journal-title>Acta neuropathologica</journal-title></journal-title-group><issn pub-type="ppub">0001-6322</issn><issn pub-type="epub">1432-0533</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24442578</article-id><article-id pub-id-type="pmc">4003885</article-id><article-id pub-id-type="doi">10.1007/s00401-013-1239-x</article-id><article-id pub-id-type="manuscript">NIHMS568688</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>TMEM106B</italic> is a genetic modifier of frontotemporal lobar degeneration with <italic>C9orf72</italic> hexanucleotide repeat expansions</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gallagher</surname><given-names>Michael D.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Suh</surname><given-names>Eunran</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Grossman</surname><given-names>Murray</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Elman</surname><given-names>Lauren</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>McCluskey</surname><given-names>Leo</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Van Swieten</surname><given-names>John C.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Al-Sarraj</surname><given-names>Safa</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Neumann</surname><given-names>Manuela</given-names></name><xref ref-type="aff" rid="A7">7</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Gelpi</surname><given-names>Ellen</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Ghetti</surname><given-names>Bernardino</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Rohrer</surname><given-names>Jonathan D.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Halliday</surname><given-names>Glenda</given-names></name><xref ref-type="aff" rid="A12">12</xref><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Van Broeckhoven</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Seilhean</surname><given-names>Danielle</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Pamela J.</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Frosch</surname><given-names>Matthew P.</given-names></name><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><collab>International Collaboration for Frontotemporal Lobar Degeneration</collab><xref rid="FN2" ref-type="author-notes">†</xref></contrib><contrib contrib-type="author"><name><surname>Trojanowski</surname><given-names>John Q.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Virginia M.Y.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Van Deerlin</surname><given-names>Vivianna</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Chen-Plotkin</surname><given-names>Alice S.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib></contrib-group><aff id="A1"><label>1</label>Cell & Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</aff><aff id="A2"><label>2</label>Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</aff><aff id="A3"><label>3</label>Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA</aff><aff id="A4"><label>4</label>Erasmus Medical Centre, s’Gravendijkwal 230, Rotterdam</aff><aff id="A5"><label>5</label>Alzheimercenter Vumc, Boelelaan 1118, Amsterdam</aff><aff id="A6"><label>6</label>King’s College Hospital, London</aff><aff id="A7"><label>7</label>University of Tübingen, Calwerstr. 3, 72072 Tübingen, Germany</aff><aff id="A8"><label>8</label>German Center for Neurodegenerative Diseases (DZNE)</aff><aff id="A9"><label>9</label>Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de Medicina, c/Casanova 143, planta 0, ala sur. 08036 Barcelona, Spain</aff><aff id="A10"><label>10</label>Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN</aff><aff id="A11"><label>11</label>Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK</aff><aff id="A12"><label>12</label>Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia</aff><aff id="A13"><label>13</label>Faculty of Medicine, University of New South Wales, Australia</aff><aff id="A14"><label>14</label>Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerpen, Belgium</aff><aff id="A15"><label>15</label>University Pierre et Marie Curie (UPMC)-Sorbonne University, France</aff><aff id="A16"><label>16</label>University of Sheffield, UK</aff><aff id="A17"><label>17</label>Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA</aff><author-notes><corresp id="FN1">Correspondence to: Alice Chen-Plotkin, Department of Neurology, 3 W Gates, 3400 Spruce St, Philadelphia, PA 19104, <email>chenplot@mail.med.upenn.edu</email>, Telephone: 215-573-7193, Fax: 215-349-5579</corresp><fn id="FN2"><label>†</label><p>see International Collaboration for Frontotemporal Lobar Degeneration section for full list of contributors</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>8</day><month>4</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>19</day><month>1</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>3</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>29</day><month>4</month><year>2014</year></pub-date><volume>127</volume><issue>3</issue><fpage>407</fpage><lpage>418</lpage><pmc-comment>elocation-id from pubmed: 10.1007/s00401-013-1239-x</pmc-comment>
<abstract><p id="P1">Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (<italic>C9orf72)</italic> have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at <italic>TMEM106B</italic> influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP). Previous reports have shown that <italic>TMEM106B</italic> is a genetic modifier of FTLD-TDP caused by progranulin (<italic>GRN</italic>) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with <italic>C9orf72</italic> expansions (n=14), with the major allele correlated with later age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with <italic>C9orf72</italic> expansions (n=75), again finding that the major allele associates with later age at death (p=0.016), as well as later age at onset (p=0.019). In contrast, <italic>TMEM106B</italic> genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for <italic>GRN</italic> mutations or <italic>C9orf72</italic> expansions. Thus, <italic>TMEM106B</italic> is a genetic modifier of FTLD with <italic>C9orf72</italic> expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in <italic>C9orf72</italic> expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.</p></abstract><kwd-group><kwd>TMEM106B</kwd><kwd>C9orf72</kwd><kwd>frontotemporal dementia</kwd><kwd>frontotemporal lobar degeneration</kwd><kwd>amyotrophic lateral sclerosis</kwd><kwd>genetic modifier</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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