Investigation of C9orf72 in 4 Neurodegenerative Disorders
Identifieur interne : 001197 ( Main/Exploration ); précédent : 001196; suivant : 001198Investigation of C9orf72 in 4 Neurodegenerative Disorders
Auteurs : Zhengrui Xi ; Lorne Zinman ; Yakov Grinberg ; Danielle Moreno ; Christine Sato ; Juan M. Bilbao ; Mahdi Ghani ; Isabel Hernández ; Agustín Ruiz ; Mercè Boada ; Francisco J. Mor N ; Anthony E. Lang ; Connie Marras ; Amalia Bruni ; Rosanna Colao ; Raffaele G. Maletta ; Gianfranco Puccio ; Innocenzo Rainero ; Lorenzo Pinessi ; Daniela Galimberti ; Karen E. Morrison ; Catriona Moorby ; Joanne D. Stockton ; Mario Masellis ; Sandra E. Black ; Lili-Naz Hazrati ; Yan Liang ; Jan Van Haersma De With ; Luis Fornazzari ; Roque Villagra ; Ricardo Rojas-Garcia ; Jordi Clarim N ; Richard Mayeux ; Janice Robertson ; Peter St George-Hyslop ; Ekaterina RogaevaSource :
- Archives of neurology [ 0003-9942 ] ; 2012.
Abstract
To estimate the allele frequency of
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained
Hospitals specializing in neurodegenerative disorders.
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the
The expansion frequency.
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
Url:
DOI: 10.1001/archneurol.2012.2016
PubMed: 22964832
PubMed Central: 4005900
Affiliations:
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Bilbao</name></author><author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name></author><author><name sortKey="Hernandez, Isabel" sort="Hernandez, Isabel" uniqKey="Hernandez I" first="Isabel" last="Hernández">Isabel Hernández</name></author><author><name sortKey="Ruiz, Agustin" sort="Ruiz, Agustin" uniqKey="Ruiz A" first="Agustín" last="Ruiz">Agustín Ruiz</name></author><author><name sortKey="Boada, Merce" sort="Boada, Merce" uniqKey="Boada M" first="Mercè" last="Boada">Mercè Boada</name></author><author><name sortKey="Mor N, Francisco J" sort="Mor N, Francisco J" uniqKey="Mor N F" first="Francisco J." last="Mor N">Francisco J. Mor N</name></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name></author><author><name sortKey="Marras, Connie" sort="Marras, Connie" uniqKey="Marras C" first="Connie" last="Marras">Connie Marras</name></author><author><name sortKey="Bruni, Amalia" sort="Bruni, Amalia" uniqKey="Bruni A" first="Amalia" last="Bruni">Amalia Bruni</name></author><author><name sortKey="Colao, Rosanna" sort="Colao, Rosanna" uniqKey="Colao R" first="Rosanna" last="Colao">Rosanna Colao</name></author><author><name sortKey="Maletta, Raffaele G" sort="Maletta, Raffaele G" uniqKey="Maletta R" first="Raffaele G." last="Maletta">Raffaele G. Maletta</name></author><author><name sortKey="Puccio, Gianfranco" sort="Puccio, Gianfranco" uniqKey="Puccio G" first="Gianfranco" last="Puccio">Gianfranco Puccio</name></author><author><name sortKey="Rainero, Innocenzo" sort="Rainero, Innocenzo" uniqKey="Rainero I" first="Innocenzo" last="Rainero">Innocenzo Rainero</name></author><author><name sortKey="Pinessi, Lorenzo" sort="Pinessi, Lorenzo" uniqKey="Pinessi L" first="Lorenzo" last="Pinessi">Lorenzo Pinessi</name></author><author><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name></author><author><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E." last="Morrison">Karen E. Morrison</name></author><author><name sortKey="Moorby, Catriona" sort="Moorby, Catriona" uniqKey="Moorby C" first="Catriona" last="Moorby">Catriona Moorby</name></author><author><name sortKey="Stockton, Joanne D" sort="Stockton, Joanne D" uniqKey="Stockton J" first="Joanne D." last="Stockton">Joanne D. Stockton</name></author><author><name sortKey="Masellis, Mario" sort="Masellis, Mario" uniqKey="Masellis M" first="Mario" last="Masellis">Mario Masellis</name></author><author><name sortKey="Black, Sandra E" sort="Black, Sandra E" uniqKey="Black S" first="Sandra E." last="Black">Sandra E. Black</name></author><author><name sortKey="Hazrati, Lili Naz" sort="Hazrati, Lili Naz" uniqKey="Hazrati L" first="Lili-Naz" last="Hazrati">Lili-Naz Hazrati</name></author><author><name sortKey="Liang, Yan" sort="Liang, Yan" uniqKey="Liang Y" first="Yan" last="Liang">Yan Liang</name></author><author><name sortKey="Van Haersma De With, Jan" sort="Van Haersma De With, Jan" uniqKey="Van Haersma De With J" first="Jan" last="Van Haersma De With">Jan Van Haersma De With</name></author><author><name sortKey="Fornazzari, Luis" sort="Fornazzari, Luis" uniqKey="Fornazzari L" first="Luis" last="Fornazzari">Luis Fornazzari</name></author><author><name sortKey="Villagra, Roque" sort="Villagra, Roque" uniqKey="Villagra R" first="Roque" last="Villagra">Roque Villagra</name></author><author><name sortKey="Rojas Garcia, Ricardo" sort="Rojas Garcia, Ricardo" uniqKey="Rojas Garcia R" first="Ricardo" last="Rojas-Garcia">Ricardo Rojas-Garcia</name></author><author><name sortKey="Clarim N, Jordi" sort="Clarim N, Jordi" uniqKey="Clarim N J" first="Jordi" last="Clarim N">Jordi Clarim N</name></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name></author><author><name sortKey="Robertson, Janice" sort="Robertson, Janice" uniqKey="Robertson J" first="Janice" last="Robertson">Janice Robertson</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name></author></analytic><series><title level="j">Archives of neurology</title><idno type="ISSN">0003-9942</idno><idno type="eISSN">1538-3687</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objective</title><p id="P1">To estimate the allele frequency of <italic>C9orf72</italic> (G<sub>4</sub>C<sub>2</sub>) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).</p></sec><sec id="S2"><title>Design</title><p id="P2">The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained <italic>APOE</italic> genotypes and <italic>MAPT</italic> H1/H2 haplotypes.</p></sec><sec id="S3"><title>Setting</title><p id="P3">Hospitals specializing in neurodegenerative disorders.</p></sec><sec id="S4"><title>Subjects</title><p id="P4">We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the <italic>LRRK2</italic> G2019S mutation.</p></sec><sec id="S5"><title>Main Outcome Measure</title><p id="P5">The expansion frequency.</p></sec><sec id="S6"><title>Results</title><p id="P6">Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with <italic>MAPT, APOE</italic>, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the <italic>C9orf72</italic> locus.</p></sec><sec id="S7"><title>Conclusions</title><p id="P7">The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Bilbao, Juan M" sort="Bilbao, Juan M" uniqKey="Bilbao J" first="Juan M." last="Bilbao">Juan M. Bilbao</name><name sortKey="Black, Sandra E" sort="Black, Sandra E" uniqKey="Black S" first="Sandra E." last="Black">Sandra E. Black</name><name sortKey="Boada, Merce" sort="Boada, Merce" uniqKey="Boada M" first="Mercè" last="Boada">Mercè Boada</name><name sortKey="Bruni, Amalia" sort="Bruni, Amalia" uniqKey="Bruni A" first="Amalia" last="Bruni">Amalia Bruni</name><name sortKey="Clarim N, Jordi" sort="Clarim N, Jordi" uniqKey="Clarim N J" first="Jordi" last="Clarim N">Jordi Clarim N</name><name sortKey="Colao, Rosanna" sort="Colao, Rosanna" uniqKey="Colao R" first="Rosanna" last="Colao">Rosanna Colao</name><name sortKey="Fornazzari, Luis" sort="Fornazzari, Luis" uniqKey="Fornazzari L" first="Luis" last="Fornazzari">Luis Fornazzari</name><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name><name sortKey="Grinberg, Yakov" sort="Grinberg, Yakov" uniqKey="Grinberg Y" first="Yakov" last="Grinberg">Yakov Grinberg</name><name sortKey="Hazrati, Lili Naz" sort="Hazrati, Lili Naz" uniqKey="Hazrati L" first="Lili-Naz" last="Hazrati">Lili-Naz Hazrati</name><name sortKey="Hernandez, Isabel" sort="Hernandez, Isabel" uniqKey="Hernandez I" first="Isabel" last="Hernández">Isabel Hernández</name><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name><name sortKey="Liang, Yan" sort="Liang, Yan" uniqKey="Liang Y" first="Yan" last="Liang">Yan Liang</name><name sortKey="Maletta, Raffaele G" sort="Maletta, Raffaele G" uniqKey="Maletta R" first="Raffaele G." last="Maletta">Raffaele G. Maletta</name><name sortKey="Marras, Connie" sort="Marras, Connie" uniqKey="Marras C" first="Connie" last="Marras">Connie Marras</name><name sortKey="Masellis, Mario" sort="Masellis, Mario" uniqKey="Masellis M" first="Mario" last="Masellis">Mario Masellis</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Moorby, Catriona" sort="Moorby, Catriona" uniqKey="Moorby C" first="Catriona" last="Moorby">Catriona Moorby</name><name sortKey="Mor N, Francisco J" sort="Mor N, Francisco J" uniqKey="Mor N F" first="Francisco J." last="Mor N">Francisco J. Mor N</name><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name><name sortKey="Morrison, Karen E" sort="Morrison, Karen E" uniqKey="Morrison K" first="Karen E." last="Morrison">Karen E. Morrison</name><name sortKey="Pinessi, Lorenzo" sort="Pinessi, Lorenzo" uniqKey="Pinessi L" first="Lorenzo" last="Pinessi">Lorenzo Pinessi</name><name sortKey="Puccio, Gianfranco" sort="Puccio, Gianfranco" uniqKey="Puccio G" first="Gianfranco" last="Puccio">Gianfranco Puccio</name><name sortKey="Rainero, Innocenzo" sort="Rainero, Innocenzo" uniqKey="Rainero I" first="Innocenzo" last="Rainero">Innocenzo Rainero</name><name sortKey="Robertson, Janice" sort="Robertson, Janice" uniqKey="Robertson J" first="Janice" last="Robertson">Janice Robertson</name><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><name sortKey="Rojas Garcia, Ricardo" sort="Rojas Garcia, Ricardo" uniqKey="Rojas Garcia R" first="Ricardo" last="Rojas-Garcia">Ricardo Rojas-Garcia</name><name sortKey="Ruiz, Agustin" sort="Ruiz, Agustin" uniqKey="Ruiz A" first="Agustín" last="Ruiz">Agustín Ruiz</name><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><name sortKey="Stockton, Joanne D" sort="Stockton, Joanne D" uniqKey="Stockton J" first="Joanne D." last="Stockton">Joanne D. Stockton</name><name sortKey="Van Haersma De With, Jan" sort="Van Haersma De With, Jan" uniqKey="Van Haersma De With J" first="Jan" last="Van Haersma De With">Jan Van Haersma De With</name><name sortKey="Villagra, Roque" sort="Villagra, Roque" uniqKey="Villagra R" first="Roque" last="Villagra">Roque Villagra</name><name sortKey="Xi, Zhengrui" sort="Xi, Zhengrui" uniqKey="Xi Z" first="Zhengrui" last="Xi">Zhengrui Xi</name><name sortKey="Zinman, Lorne" sort="Zinman, Lorne" uniqKey="Zinman L" first="Lorne" last="Zinman">Lorne Zinman</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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