Title | Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Dewan R, Chia R, Ding J, Hickman RA, Stein TD, Abramzon Y, Ahmed S, Sabir MS, Portley MK, Tucci A, Ibáñez K, Shankaracharya FNU, Keagle P, Rossi G, Caroppo P, Tagliavini F, Waldo ML, Johansson PM, Nilsson CF, Rowe JB, Benussi L, Binetti G, Ghidoni R, Jabbari E, Viollet C, Glass JD, Singleton AB, Silani V, Ross OA, Ryten M, Torkamani A, Tanaka T, Ferrucci L, Resnick SM, Pickering-Brown S, Brady CB, Kowal N, Hardy JA, Van Deerlin V, Vonsattel JPaul, Harms MB, Morris HR, Ferrari R, Landers JE, Chiò A, J Gibbs R, Dalgard CL, Scholz SW, Traynor BJ |
Corporate Authors | American Genome Center(TAGC), FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium(iAFGC), International FTD Genetics Consortium(IFGC), International LBD Genomics Consortium(iLBDGC), NYGC ALS Consortium, PROSPECT Consortium |
Journal | Neuron |
Volume | 109 |
Issue | 3 |
Pagination | 448-460.e4 |
Date Published | 2021 02 03 |
ISSN | 1097-4199 |
Keywords | Amyotrophic Lateral Sclerosis, DNA Repeat Expansion, Frontotemporal Dementia, Humans, Huntingtin Protein, Mutation, Whole Genome Sequencing |
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 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. |
DOI | 10.1016/j.neuron.2020.11.005 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/33242422?dopt=Abstract |
page_expo | External |
Alternate Journal | Neuron |
PubMed ID | 33242422 |
PubMed Central ID | PMC7864894 |
Grant List | P30 AG013854 / AG / NIA NIH HHS / United States K08 AG065463 / AG / NIA NIH HHS / United States ZIA NS003034 / ImNIH / Intramural NIH HHS / United States 103838 / WT_ / Wellcome Trust / United Kingdom MR/L501529/1 / MRC_ / Medical Research Council / United Kingdom G0600974 / MRC_ / Medical Research Council / United Kingdom / DH_ / Department of Health / United Kingdom R01 NS073873 / NS / NINDS NIH HHS / United States P30 AG066462 / AG / NIA NIH HHS / United States P01 AG066597 / AG / NIA NIH HHS / United States ZIA AG000935 / ImNIH / Intramural NIH HHS / United States J-0901 / PUK_ / Parkinson's UK / United Kingdom ZIA AG000933 / ImNIH / Intramural NIH HHS / United States MC_EX_MR/N50192X/1 / MRC_ / Medical Research Council / United Kingdom MC_UU_00005/12 / MRC_ / Medical Research Council / United Kingdom MR/N008324/1 / MRC_ / Medical Research Council / United Kingdom R01 NS115144 / NS / NINDS NIH HHS / United States P30 AG066507 / AG / NIA NIH HHS / United States MR/S000992/1 / MRC_ / Medical Research Council / United Kingdom I01 BX002466 / BX / BLRD VA / United States MC_U105597119 / MRC_ / Medical Research Council / United Kingdom AL-CHALABI/APR15/844-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom ZIA AG000934 / ImNIH / Intramural NIH HHS / United States K-1501 / PUK_ / Parkinson's UK / United Kingdom MR/L016397/1 / MRC_ / Medical Research Council / United Kingdom ZIA NS003154 / ImNIH / Intramural NIH HHS / United States MR/R024804/1 / MRC_ / Medical Research Council / United Kingdom / WT_ / Wellcome Trust / United Kingdom MR/S006753/1 / MRC_ / Medical Research Council / United Kingdom P30 AG066514 / AG / NIA NIH HHS / United States MR/M024962/1 / MRC_ / Medical Research Council / United Kingdom |
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