Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
 
American Genome Center (TAGC); FALS Sequencing Consortium; The Genomics England Research Consortium; The International ALS/FTD Genomics Consortium (iAFGC); The International FTD Genetics Consortium (IFGC); The International LBD Genomics Consortium (iLBDGC); NYGC ALS Consortium; The PROSPECT Consortium
(2021) Neuron, volume 109, issue 3, pp. 448 - 460.e4
(Article)
Abstract
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene ... read more
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Keywords: Amyotrophic Lateral Sclerosis/genetics, DNA Repeat Expansion, Frontotemporal Dementia/genetics, Humans, Huntingtin Protein/genetics, Mutation, Whole Genome Sequencing, huntingtin, whole-genome sequencing, frontotemporal dementia, repeat expansions, amyotrophic lateral sclerosis, General Neuroscience, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural, Journal Article, Research Support, N.I.H., Extramural
DOI: https://doi.org/10.1016/j.neuron.2020.11.005
ISSN: 0896-6273
Publisher: Cell Press
Note: Funding Information: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke, project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute. This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee (P30 AG066462-01, PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America. J.B.R. is supported by the Wellcome Trust (103838) and National Institute for Health Research Cambridge Biomedical Research Centre. J.E.L. was supported by the National Institutes of Health/National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001. The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459) and the Tow Foundation. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (https://hpc.nih.gov). L.B. G.B. C.B.B. P.C. A.C. R.F. L.F. R.G. J.D.G. J.A.H. M.B.H. R.A.H. K.I. E.J. P.M.J. N.K. J.E.L. H.R.M. C.F.N. S.P.-B. S.M.R. O.A.R. G.R. J.B.R. M.R. S.W.S. V.S. A.B.S. T.D.S. F.T. T.T. A. Torkamani, B.J.T. V.V. J.P.V. and M.L.W. collected and prepared the samples and performed the clinical evaluations. Y.A. S.A. R.C. A.C. C.L.D. R.D. J.D. R.F. J.G. M.B.H. R.A.H. P.K. J.E.L. H.R.M. M.K.P. M.S.S. T.D.S. A. Tucci, V.V. C.V. J.P.V. and S. conducted the experiments and the data analysis. R.D. S.W.S. and B.J.T. wrote the manuscript. A.C. R.F. L.F. J.G. J.A.H. M.B.H. J.E.L. H.R.M. A.B.S. S.W.S. and B.J.T. designed and supervised the experiments. S.P.-B. A.B.S. J.A.H. H.R.M. and B.J.T. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9 or f72. S.W.S. serves on the scientific advisory council of the Lewy Body Dementia Association and is an editorial board member for the Journal of Parkinson's Disease. B.J.T. is an editorial board member for JAMA Neurology, JNNP, and Neurobiology of Aging. V.S. is on the journal editorial boards of Amyotrophic Lateral Sclerosis, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. He has also received compensation for consulting services and speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon. J.B.R. is an editor for Brain and has received compensation for consulting services from Asceneuron, Biogen, UCB, Astex, and SV Health. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie. Funding Information: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health ( National Institute on Aging , National Institute of Neurological Disorders and Stroke , project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute . This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee ( P30 AG066462-01 , PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America . J.B.R. is supported by the Wellcome Trust ( 103838 ) and National Institute for Health Research Cambridge Biomedical Research Centre . J.E.L. was supported by the National Institutes of Health /National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001 . The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459 ) and the Tow Foundation . This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health , Bethesda, MD ( https://hpc.nih.gov ). Publisher Copyright: © 2020
(Peer reviewed)