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

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Dokumenter

  • Pathogenic

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  • Ramita Dewan
  • Ruth Chia
  • Jinhui Ding
  • Richard A. Hickman
  • Thor D. Stein
  • Yevgeniya Abramzon
  • Sarah Ahmed
  • Marya S. Sabir
  • Makayla K. Portley
  • Arianna Tucci
  • Kristina Ibáñez
  • F. N.U. Shankaracharya
  • Pamela Keagle
  • Giacomina Rossi
  • Paola Caroppo
  • Fabrizio Tagliavini
  • Maria L. Waldo
  • Per M. Johansson
  • Christer F. Nilsson
  • Adelani Adeleye
  • Camille Alba
  • Dagmar Bacikova
  • Daniel N. Hupalo
  • Elisa Mc Grath Martinez
  • Harvey B. Pollard
  • Gauthaman Sukumar
  • Anthony R. Soltis
  • Meila Tuck
  • Xijun Zhang
  • Matthew D. Wilkerson
  • Bradley N. Smith
  • Nicola Ticozzi
  • Claudia Fallini
  • Athina Soragia Gkazi
  • Simon D. Topp
  • Jason Kost
  • Emma L. Scotter
  • Kevin P. Kenna
  • Jack W. Miller
  • Cinzia Tiloca
  • Caroline Vance
  • Eric W. Danielson
  • Claire Troakes
  • Claudia Colombrita
  • Safa Al-Sarraj
  • Elizabeth A. Lewis
  • Nielsen, Jørgen Erik
  • Lynne E. Hjermind
  • Regina H. Reynolds
  • Rowe, James Benedict
  • The PROSPECT Consortium
  • The American Genome Center (TAGC)
  • The 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), The NYGC ALS Consortium
  • the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank

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 were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

OriginalsprogEngelsk
TidsskriftNeuron
Vol/bind109
Udgave nummer3
Sider (fra-til)448-460
Antal sider13
ISSN0896-6273
DOI
StatusUdgivet - 2021

Bibliografisk 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

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