A Pan‐European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats
Julie van der Zee,Ilse Gijselinck,Lubina Dillen,Tim Van Langenhove,Jessie Theuns,Sebastiaan Engelborghs,Stéphanie Philtjens,Mathieu Vandenbulcke,Kristel Sleegers,Anne Sieben,Anne Sieben,Veerle Bäumer,Githa Maes,Ellen Corsmit,Barbara Borroni,Alessandro Padovani,Silvana Archetti,Robert Perneczky,Janine Diehl-Schmid,Alexandre de Mendonça,Gabriel Miltenberger-Miltenyi,Sónia Pereira,José Pimentel,Benedetta Nacmias,Silvia Bagnoli,Sandro Sorbi,Caroline Graff,Caroline Graff,Huei-Hsin Chiang,Marie Westerlund,Raquel Sánchez-Valle,Albert Lladó,Ellen Gelpi,Isabel Santana,Maria Rosário Almeida,Beatriz Santiago,Giovanni B. Frisoni,Orazio Zanetti,Cristian Bonvicini,Matthis Synofzik,Walter Maetzler,Jennifer Müller vom Hagen,Ludger Schöls,Michael T. Heneka,Michael T. Heneka,Frank Jessen,Frank Jessen,Radoslav Matej,Eva Parobkova,Gabor G. Kovacs,Thomas Ströbel,Stayko Sarafov,Ivailo Tournev,Ivailo Tournev,Albena Jordanova,Adrian Danek,Thomas Arzberger,Gian Maria Fabrizi,Silvia Testi,Eric Salmon,Patrick Santens,Jean-Jacques Martin,Patrick Cras,Rik Vandenberghe,Peter Paul De Deyn,Marc Cruts,Christine Van Broeckhoven,Peter Paul De Deyn,Alfredo Ramirez,Delia Kurzwelly,Carmen Sachtleben,Wolfgang Mairer,Clara Firmo,Anna Antonell,José Luis Molinuevo,Anne Kinhult Ståhlbom,Håkan Thonberg,Inger Nennesmo,Anne Börjesson-Hanson,Valentina Bessi,Irene Piaceri,Maria Helena Ribeiro,Catarina R. Oliveira,João Massano,Carolina Garret,Paula Pires,Adrian Danel,Sergio Ferrari,Tiziana Cavallaro +88 more
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TLDR
In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism.Abstract:
We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.read more
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Defeating Alzheimer's disease and other dementias: a priority for European science and society
Bengt Winblad,Bengt Winblad,Philippe Amouyel,Sandrine Andrieu,Clive Ballard,Carol Brayne,Henry Brodaty,Angel Cedazo-Minguez,Bruno Dubois,David Edvardsson,David Edvardsson,Howard Feldman,Laura Fratiglioni,Giovanni B. Frisoni,Serge Gauthier,Jean Georges,Caroline Graff,Caroline Graff,Khalid Iqbal,Frank Jessen,Frank Jessen,Gunilla Johansson,Linus Jönsson,Miia Kivipelto,Miia Kivipelto,Martin Knapp,Francesca Mangialasche,René J. F. Melis,Agneta Nordberg,Agneta Nordberg,Marcel G. M. Olde Rikkert,Chengxuan Qiu,Thomas P. Sakmar,Thomas P. Sakmar,Philip Scheltens,Lon S. Schneider,Reisa A. Sperling,Lars O. Tjernberg,Gunhild Waldemar,Anders Wimo,Henrik Zetterberg,Henrik Zetterberg +41 more
TL;DR: This poster aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about the physical and cognitive properties of Alzheimer's disease and other dementias.
Journal ArticleDOI
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Kohji Mori,Shih-Ming Weng,Thomas Arzberger,Stephanie May,Kristin Rentzsch,Elisabeth Kremmer,Bettina Schmid,Bettina Schmid,Hans A. Kretzschmar,Marc Cruts,Christine Van Broeckhoven,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +14 more
TL;DR: It is found that characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown, and a new class of proteins links a common genetic mutation to the predominant pathology in certain neurodegenerative diseases.
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Protein aggregation in amyotrophic lateral sclerosis
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Journal ArticleDOI
Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins
Kohji Mori,Thomas Arzberger,Thomas Arzberger,Friedrich A. Grässer,Ilse Gijselinck,Stephanie May,Kristin Rentzsch,Shih Ming Weng,Martin H. Schludi,Julie van der Zee,Marc Cruts,Christine Van Broeckhoven,Elisabeth Kremmer,Hans A. Kretzschmar,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +17 more
TL;DR: The data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion.
Journal ArticleDOI
C9orf72 -mediated ALS and FTD: multiple pathways to disease
Rubika Balendra,Adrian M. Isaacs +1 more
TL;DR: It is suggested that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-aut autonomous and non-cell-autonomous effects contributes to disease progression.
References
More filters
Book ChapterDOI
Primer3 on the WWW for general users and for biologist programmers.
Steve Rozen,Helen Skaletsky +1 more
TL;DR: This chapter assumes acquaintance with the principles and practice of PCR, as outlined in, for example, refs.
Journal ArticleDOI
Frontotemporal lobar degeneration A consensus on clinical diagnostic criteria
David Neary,Julie S. Snowden,L. Gustafson,U. Passant,Donald T. Stuss,Sandra E. Black,Morris Freedman,Andrew Kertesz,Philippe Robert,Marilyn S. Albert,Kyle B. Boone,Bruce L. Miller,Jeffrey L. Cummings,D. F. Benson +13 more
TL;DR: Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotem temporal lobar degeneration and ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders.
Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
Elisa Majounie,Alan E. Renton,Kin Y. Mok,Elise G.P. Dopper,Elise G.P. Dopper,Adrian James Waite,Sara Rollinson,Adriano Chiò,Gabriella Restagno,Nayia Nicolaou,Nayia Nicolaou,Javier Simón-Sánchez,Javier Simón-Sánchez,John C. van Swieten,John C. van Swieten,Yevgeniya Abramzon,Janel O. Johnson,Michael Sendtner,Roger Pamphlett,Richard W. Orrell,Simon Mead,Katie C. L. Sidle,Henry Houlden,Jonathan D. Rohrer,Karen E. Morrison,Hardev Pall,Kevin Talbot,Olaf Ansorge,Dena G. Hernandez,Sampath Arepalli,Mario Sabatelli,Gabriele Mora,Massimo Corbo,Fabio Giannini,Andrea Calvo,Elisabet Englund,Giuseppe Borghero,Gian Luca Floris,Anne M. Remes,Hannu Laaksovirta,Leo McCluskey,John Q. Trojanowski,Vivianna M. Van Deerlin,Gerard D. Schellenberg,Mike A. Nalls,Vivian E. Drory,Chin-Song Lu,Chin-Song Lu,Tu-Hsueh Yeh,Tu-Hsueh Yeh,Hiroyuki Ishiura,Yuji Takahashi,Shoji Tsuji,Isabelle Le Ber,Isabelle Le Ber,Isabelle Le Ber,Alexis Brice,Alexis Brice,Alexis Brice,Carsten Drepper,Nigel Williams,Janine Kirby,Pamela J. Shaw,John Hardy,Pentti J. Tienari,Peter Heutink,Huw R. Morris,Huw R. Morris,Huw R. Morris,Stuart Pickering-Brown,Bryan J. Traynor,Bryan J. Traynor +71 more
TL;DR: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD, suggesting a one-off expansion occurring about 1500 years ago.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
Elisa Majounie,Alan E. Renton,Kin Y. Mok,Elise G.P. Dopper,Elise G.P. Dopper,Adrian James Waite,Sara Rollinson,Adriano Chiò,Gabriella Restagno,Nayia Nicolaou,Nayia Nicolaou,Javier Simón-Sánchez,Javier Simón-Sánchez,John C. van Swieten,John C. van Swieten,Yevgeniya Abramzon,Janel O. Johnson,Michael Sendtner,Roger Pamphlett,Richard W. Orrell,Simon Mead,Katie C. L. Sidle,Henry Houlden,Jonathan D. Rohrer,Karen E. Morrison,Hardev Pall,Kevin Talbot,Olaf Ansorge,Dena G. Hernandez,Sampath Arepalli,Mario Sabatelli,Gabriele Mora,Massimo Corbo,Fabio Giannini,Andrea Calvo,Elisabet Englund,Giuseppe Borghero,Gian Luca Floris,Anne M. Remes,Hannu Laaksovirta,Leo McCluskey,John Q. Trojanowski,Vivianna M. Van Deerlin,Gerard D. Schellenberg,Mike A. Nalls,Vivian E. Drory,Chin-Song Lu,Chin-Song Lu,Tu-Hsueh Yeh,Tu-Hsueh Yeh,Hiroyuki Ishiura,Yuji Takahashi,Shoji Tsuji,Isabelle Le Ber,Isabelle Le Ber,Isabelle Le Ber,Alexis Brice,Alexis Brice,Alexis Brice,Carsten Drepper,Nigel Williams,Janine Kirby,Pamela J. Shaw,John Hardy,Pentti J. Tienari,Peter Heutink,Huw R. Morris,Huw R. Morris,Huw R. Morris,Stuart Pickering-Brown,Bryan J. Traynor,Bryan J. Traynor +71 more