Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Janel O. Johnson,Jessica Mandrioli,Michael Benatar,Yevgeniya Abramzon,Vivianna M. Van Deerlin,John Q. Trojanowski,J. Raphael Gibbs,J. Raphael Gibbs,Maura Brunetti,Susan Gronka,Joanne Wuu,Jinhui Ding,Leo McCluskey,Maria Martinez-Lage,Dana Falcone,Dena G. Hernandez,Dena G. Hernandez,Sampath Arepalli,Sean Chong,Jennifer C. Schymick,Jeffrey D. Rothstein,Francesco Landi,Yong Dong Wang,Andrea Calvo,Gabriele Mora,Mario Sabatelli,Maria Rosaria Monsurrò,Stefania Battistini,Fabrizio Salvi,Rossella Spataro,Patrizia Sola,Giuseppe Borghero,Giuliana Galassi,Sonja W. Scholz,Sonja W. Scholz,J. Paul Taylor,Gabriella Restagno,Adriano Chiò,Bryan J. Traynor,Bryan J. Traynor +39 more
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TLDR
Exome sequencing data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neurons degeneration.About:
This article is published in Neuron.The article was published on 2010-12-09 and is currently open access. It has received 1040 citations till now. The article focuses on the topics: Valosin-containing protein & Multisystem proteinopathy.read more
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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
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
Exome sequencing as a tool for Mendelian disease gene discovery
Michael J. Bamshad,Sarah B. Ng,Abigail W. Bigham,Abigail W. Bigham,Holly K. Tabor,Holly K. Tabor,Mary J. Emond,Deborah A. Nickerson,Jay Shendure +8 more
TL;DR: Experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders and set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.
Journal ArticleDOI
Decoding ALS: from genes to mechanism
TL;DR: Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified, and emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking.
Journal ArticleDOI
Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
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.
References
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Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
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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.
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