The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter
Ilse Gijselinck,S. Van Mossevelde,J. van der Zee,Anne Sieben,Anne Sieben,Sebastiaan Engelborghs,J. De Bleecker,Adrian Ivanoiu,Olivier Deryck,Dieter Edbauer,Dieter Edbauer,Ming Zhang,Bavo Heeman,Veerle Bäumer,M Van den Broeck,Maria Mattheijssens,K. Peeters,Ekaterina Rogaeva,P. De Jonghe,Patrick Cras,Jean-Jacques Martin,P.P. De Deyn,Marc Cruts,C. Van Broeckhoven +23 more
TLDR
It is shown that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain- of-function.Abstract:
Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD–ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45–78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent–child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7–24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2–6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.read more
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Journal ArticleDOI
Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs
Jie Jiang,Jie Jiang,Qiang Zhu,Tania F. Gendron,Shahram Saberi,Melissa McAlonis-Downes,Amanda Seelman,Jennifer E. Stauffer,Paymaan Jafar-Nejad,Kevin Drenner,Derek Schulte,Seung J. Chun,Shuying Sun,Shuo-Chien Ling,Shuo-Chien Ling,Brian Myers,Jeffery Engelhardt,Melanie Katz,Michael Baughn,Michael Baughn,Oleksandr Platoshyn,Oleksandr Platoshyn,Martin Marsala,Martin Marsala,Martin Marsala,Andrew T. Watt,Charles J. Heyser,M. Colin Ard,Louis De Muynck,Lillian M. Daughrity,Deborah A. Swing,Lino Tessarollo,Chris J. Jung,Arnaud Delpoux,Daniel T. Utzschneider,Stephen M. Hedrick,Pieter J. de Jong,Dieter Edbauer,Philip Van Damme,Leonard Petrucelli,Christopher Shaw,C. Frank Bennett,Sandrine Da Cruz,John Ravits,Frank Rigo,Don W. Cleveland,Don W. Cleveland,Clotilde Lagier-Tourenne,Clotilde Lagier-Tourenne +48 more
TL;DR: Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits.
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.
Journal ArticleDOI
The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.
Christopher P. Webster,Emma F. Smith,Claudia S. Bauer,Annekathrin Moller,Guillaume M. Hautbergue,Laura Ferraiuolo,Monika A Myszczynska,Adrian Higginbottom,Matthew J. Walsh,Alexander J. Whitworth,Brian K. Kaspar,Kathrin Meyer,Pamela J. Shaw,Andrew J. Grierson,Kurt J. De Vos +14 more
TL;DR: The data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C 9orf72 haploinsufficiency and associated reductions in Autophagy might be the underlying cause of C9ALS/FTD‐associated p62 pathology.
Journal ArticleDOI
Detection of long repeat expansions from PCR-free whole-genome sequence data.
Egor Dolzhenko,Joke J.F.A. van Vugt,Richard Shaw,Mitchell A. Bekritsky,Marka van Blitterswijk,Giuseppe Narzisi,Subramanian S. Ajay,Vani Rajan,Bryan R. Lajoie,Nathan H. Johnson,Zoya Kingsbury,Sean Humphray,Raymond D. Schellevis,William J. Brands,Matthew B. Baker,Rosa Rademakers,Maarten Kooyman,Gijs H.P. Tazelaar,Michael A. van Es,Russell L. McLaughlin,Russell L. McLaughlin,William Sproviero,Aleksey Shatunov,Ashley R. Jones,Ahmad Al Khleifat,Alan M. Pittman,Sarah Morgan,Orla Hardiman,Orla Hardiman,Ammar Al-Chalabi,Christopher Shaw,Bradley N. Smith,Edmund J. Neo,Karen E. Morrison,Pamela J. Shaw,Catherine Reeves,Lara Winterkorn,Nancy S. Wexler,Nancy S. Wexler,David E. Housman,Christopher W. Ng,Alina L. Li,Ryan J. Taft,Leonard H. van den Berg,David R. Bentley,Jan H. Veldink,Michael A. Eberle +46 more
TL;DR: A software tool called ExpansionHunter is developed that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length, and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
Journal ArticleDOI
ALS Genes in the Genomic Era and their Implications for FTD
TL;DR: This review paper presents a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants and their potential relevance to frontotemporal dementia genetic etiology and highlights emerging key molecular processes and opportunities for therapy.
References
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El Escorial revisited : revised criteria for the diagnosis of amyotrophic lateral sclerosis
TL;DR: The criteria described below represent the result of a three-day workshop, convened at Airlie Conference Center, Warrenton, Virginia on 2–4 April, 1998 by the World Federation of Neurology Research Committee on Motor Neuron Diseases, and are placed on the WFN ALS website.
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
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
Katya Rascovsky,John R. Hodges,David S. Knopman,Mario F. Mendez,Joel H. Kramer,John Neuhaus,John C. van Swieten,Harro Seelaar,Elise G.P. Dopper,Chiadi U. Onyike,Argye E. Hillis,Keith A. Josephs,Bradley F. Boeve,Andrew Kertesz,William W. Seeley,Katherine P. Rankin,Julene K. Johnson,Maria Luisa Gorno-Tempini,Howard J. Rosen,Caroline E. Prioleau-Latham,Albert Lee,Christopher M. Kipps,Christopher M. Kipps,Patricia Lillo,Olivier Piguet,Jonathan D. Rohrer,Martin N. Rossor,Jason D. Warren,Nick C. Fox,Douglas Galasko,David P. Salmon,Sandra E. Black,M.-Marsel Mesulam,Sandra Weintraub,Brad C. Dickerson,Janine Diehl-Schmid,Florence Pasquier,Vincent Deramecourt,Florence Lebert,Yolande A.L. Pijnenburg,Tiffany W. Chow,Facundo Manes,Jordan Grafman,Stefano F. Cappa,Morris Freedman,Murray Grossman,Bruce L. Miller +46 more
TL;DR: The revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotmporal lobar degeneration and reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations.
Journal ArticleDOI
Classification of primary progressive aphasia and its variants
Maria Luisa Gorno-Tempini,Maria Luisa Gorno-Tempini,Argye E. Hillis,Sandra Weintraub,Andrew Kertesz,Mario F. Mendez,Stefano F. Cappa,J. M. Ogar,Jonathan D. Rohrer,Sandra E. Black,Bradley F. Boeve,Facundo Manes,Nina F. Dronkers,Rik Vandenberghe,Katya Rascovsky,Karalyn Patterson,Bruce L. Miller,D. S. Knopman,John R. Hodges,M.-Marsel Mesulam,Murray Grossman +20 more
TL;DR: This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results.
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