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
TLDR
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.Abstract:
Background
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Methods
We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings
In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation
A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
Funding
Full funding sources listed at end of paper (see Acknowledgments).read more
Citations
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Journal ArticleDOI
State of play in amyotrophic lateral sclerosis genetics.
TL;DR: Current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1 are summarized and how each new genetic discovery is broadening the phenotype associated with the clinical entity the authors know as ALS is outlined.
Journal ArticleDOI
The changing scene of amyotrophic lateral sclerosis
TL;DR: New findings in ALS research are summarized, what they have taught us about this disease are discussed and issues that are still outstanding are examined.
Journal ArticleDOI
C9orf72 nucleotide repeat structures initiate molecular cascades of disease
Aaron R. Haeusler,Christopher J. Donnelly,Goran Periz,Eric A J Simko,Patrick G. Shaw,Min-Sik Kim,Nicholas J. Maragakis,Juan C. Troncoso,Akhilesh Pandey,Rita Sattler,Jeffrey D. Rothstein,Jiou Wang +11 more
TL;DR: It is demonstrated that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provides the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Journal ArticleDOI
The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
Ke Zhang,Christopher J. Donnelly,Aaron R. Haeusler,Jonathan C. Grima,James B. Machamer,Peter Steinwald,Elizabeth L. Daley,Sean J. Miller,Kathleen M. Cunningham,Svetlana Vidensky,Saksham Gupta,Michael A. Thomas,Ingie Hong,Shu Ling Chiu,Richard L. Huganir,Lyle W. Ostrow,Michael J. Matunis,Jiou Wang,Rita Sattler,Thomas E. Lloyd,Jeffrey D. Rothstein +20 more
TL;DR: Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes.
Journal ArticleDOI
RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
Christopher J. Donnelly,Ping Wu Zhang,Jacqueline T. Pham,Aaron R. Haeusler,Nipun A. Mistry,Svetlana Vidensky,Elizabeth L. Daley,Erin M. Poth,Benjamin Hoover,Daniel M. Fines,Nicholas J. Maragakis,Pentti J. Tienari,Leonard Petrucelli,Bryan J. Traynor,Bryan J. Traynor,Jiou Wang,Frank Rigo,C. Frank Bennett,Seth Blackshaw,Rita Sattler,Jeffrey D. Rothstein +20 more
TL;DR: Data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.
References
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Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
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.
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