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Scientists have made an exciting breakthrough in unraveling the genetic basis of two debilitating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two independent studies, published online this week by Cell Press in the journal Neuron, identify a new human genetic mutation as the most common cause of ALS and FTD identified to date. This mutation explains at least a third of all familial cases of ALS and FTD within the European population. The research provides key insight into ALS and FTD and may pave the way for development of therapeutic strategies for these currently incurable diseases.
ALS, also known as Lou Gehrig's disease, causes destruction of neurons that control voluntary movement. ALS is characterized by a progressive paralysis that often leads to death from respiratory failure within a few years of diagnosis.
FTD, the second most common cause of early-onset dementia, is associated with degeneration of the frontal and temporal lobes of the brain and leads to a dramatic deterioration in personality, language and behavior. There have been suggestions that these two disorders share some underlying genetic features.
About 10% of ALS cases and about 50% of FTD cases are thought to be inherited, and, although multiple genes have been linked with the disorders, much of the genetic risk has remained unexplained. "Each new gene implicated in the etiology of ALS or FTD provides fundamental insights into the cellular mechanisms underlying neuron degeneration, as well as facilitating disease modeling and the design and testing of targeted therapeutics," explains Dr. Bryan J. Traynor from the National Institutes of Health who is an author of one of the studies. "Identification of new genes that cause ALS or FTD is of great significance."
Recent research has linked a region on chromosome 9, called 9p21, with both ALS and FTD. Dr. Traynor's group performed an exhaustive next generation genetic analysis of this region in patients with 9p21-associated ALS or FTD, including the group of Finnish ALS patients that had previously been used to identify the association with 9p21. A second research group, led by Dr. Rosa Rademakers from the Mayo Clinic Jacksonville, performed a similar analysis using a large family with ALS and FTD linked to chromosome 9p21.
Both groups discovered a "repeat expansion" within the non-coding region of C9ORF72, a gene whose function is not known. This mutation argues that both ALS and FTD are diseases caused by defects in RNA metabolism. This idea is in line with other recent work in ALS, FTD and neurodegenerative diseases more broadly stressing RNA-driven disease pathology.
The researchers searched for clinical and pathological characteristics associated with the mutation. "Our findings suggest multiple potential disease mechanisms associated with this repeat expansion," says Dr. Rademakers. "For example, we found evidence of a previously described process where the expansion region accumulates inside the neurons as abnormal structures called RNA foci that are likely to promote disease pathogenesis. Further molecular studies are needed to explore how these mechanisms contribute to neurodegeneration."
Taken together, the findings of both studies suggest that the repeat expansion in C9ORF72 is a major cause of an unprecedented proportion of both sporadic and familial FTD and ALS cases. The mutation explains nearly half of all cases in Finland alone and at least a third of all familial FTD and ALS cases in Europeans. Importantly, the mutation was also associated with a number of non-inherited cases of ALS and FTD. "With this discovery we can now explain nearly all of familial ALS disease in Finland, which has the highest incidence of ALS in the world. In the longer term, the identification of the genetic lesion underlying chromosome 9p21-linked ALS and FTD, together with the observed high frequency in these patient populations, makes it an ideal target for drug development aimed at amelioration of the disease process," concludes Dr. Traynor.
Source 1/2
Cell Press
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
http://www.cell.com/neuron/abstract/S0896-6273%2811%2900797-5
Authors and affiliations
Alan E. Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J. Raphael Gibbs, Jennifer C. Schymick, Hannu Laaksovirta, John C. van Swieten, Liisa Myllykangas, Hannu Kalimo, Anders Paetau, Yevgeniya Abramzon, Anne M. Remes, Alice Kaganovich, Sonja W. Scholz, Jamie Duckworth, Jinhui Ding, Daniel W. Harmer, Dena G. Hernandez, Janel O. Johnson, Kin Mok, Mina Ryten, Danyah Trabzuni, Rita J. Guerreiro, Richard W. Orrell, James Neal, Alex Murray, Justin Pearson, Iris E. Jansen, David Sondervan, Harro Seelaar, Derek Blake, Kate Young, Nicola Halliwell, Janis Bennion Callister, Greg Toulson, Anna Richardson, Alex Gerhard, Julie Snowden, David Mann, David Neary, Michael 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 D. Pack, Amalia Dutra, Evgenia Pak, John Hardy, Andrew Singleton, Nigel M. Williams, Peter Heutink, Stuart Pickering-Brown, Huw R. Morris, Pentti J. Tienari, Bryan J. Trayno
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands Department of Neurology, Erasmus MC - University Medical Center Rotterdam, 3015 CE, Rotterdam, The Netherlands Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland Department of Pathology, Haartman Institute/HUSLAB, University of Helsinki and Folkhälsan Research Center (LM), Helsinki, FIN-02900, Finland Institute of Clinical Medicine, Neurology, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, FIN-90014, Finland Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA Department of Neuroscience, Georgetown University, Washington, D.C. 20057, USA Department of Neurology, Brain Sciences Institute, Johns Hopkins University, Baltimore, MD 21287, USA Illumina Inc., Hayward, CA 94545, USA Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UK Department of Pathology, Cardiff University School of Medicine, Cardiff CF14 4XN, UK Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, FIN-00014, Finland Section of Geriatrics, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, FIN-70211, Finland Neuromuscular Division, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Clinical Translational Research Division, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Department of Neuroscience, University of Turin, 10126 Turin, Italy Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, 09042 Cagliari, Italy Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy For a list of consortium members, please see the Supplemental Information online Microsoft Research, Los Angeles, CA 90024, USA Tanz Centre for Research of Neurodegenerative Diseases and Toronto Western Hospital, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA Chromosome Pathology Unit, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA Neurology (C4), University Hospital of Wales, Cardiff CF14 4XN, UK Department of Neurology, Royal Gwent Hospital, Aneurin Bevan Local Health Board, Gwent NP20 2UB, UK Corresponding author
These authors contributed equally to this work
Source 2/2
Cell Press
Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
http://www.cell.com/neuron/abstract/S0896-6273%2811%2900828-2
Authors and affiliations
Mariely DeJesus-Hernandez, Ian R. Mackenziesend email, Bradley F. Boeve, Adam L. Boxer, Matt Baker, Nicola J. Rutherford, Alexandra M. Nicholson, NiCole A. Finch, Heather Flynn, Jennifer Adamson, Naomi Kouri, Aleksandra Wojtas, Pheth Sengdy, Ging-Yuek R. Hsiung, Anna Karydas, William W. Seeley, Keith A. Josephs, Giovanni Coppola, Daniel H. Geschwind, Zbigniew K. Wszolek, Howard Feldman, David S. Knopman, Ronald C. Petersen, Bruce L. Miller, Dennis W. Dickson, Kevin B. Boylan, Neill R. Graff-Radford, Rosa Rademakers
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5C 1M9, Canada Department of Neurology, Mayo Clinic Rochester, Rochester, MN 55905, USA Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA Cytogenetics Core, Mayo Clinic Rochester, Rochester, MN 55905, USA Division of Neurology, University of British Columbia, Vancouver, BC V6T 2B5, Canada Department of Neurology and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA Department of Neurology, Mayo Clinic Florida, Jacksonville, FL 32224, USA Bristol-Myers Squibb, Neuroscience Global Clinical Research, Wallingford, CT 06492, USA Corresponding author
These authors contributed equally to this work
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