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

当前位置： X-MOL 学术 › Neuron › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Neuron ( IF 16.2 ) Pub Date : 2020-11-26 , DOI: 10.1016/j.neuron.2020.11.005
Ramita Dewan ₁ , Ruth Chia ₁ , Jinhui Ding ₂ , Richard A Hickman ₃ , Thor D Stein ₄ , Yevgeniya Abramzon ₅ , Sarah Ahmed ₆ , Marya S Sabir ₆ , Makayla K Portley ₆ , Arianna Tucci ₇ , Kristina Ibáñez ₇ , F N U Shankaracharya ₈ , Pamela Keagle ₈ , Giacomina Rossi ₉ , Paola Caroppo ₉ , Fabrizio Tagliavini ₁₀ , Maria L Waldo ₁₁ , Per M Johansson ₁₂ , Christer F Nilsson ₁₃ , , , , , , , , ₁₄ , James B Rowe ₁₄ , Luisa Benussi ₁₅ , Giuliano Binetti ₁₆ , Roberta Ghidoni ₁₅ , Edwin Jabbari ₁₇ , Coralie Viollet ₁₈ , Jonathan D Glass ₁₉ , Andrew B Singleton ₂₀ , Vincenzo Silani ₂₁ , Owen A Ross ₂₂ , Mina Ryten ₂₃ , Ali Torkamani ₂₄ , Toshiko Tanaka ₂₅ , Luigi Ferrucci ₂₅ , Susan M Resnick ₂₆ , Stuart Pickering-Brown ₂₇ , Christopher B Brady ₂₈ , Neil Kowal ₂₉ , John A Hardy ₃₀ , Vivianna Van Deerlin ₃₁ , Jean Paul Vonsattel ₃ , Matthew B Harms ₃₂ , Huw R Morris ₁₇ , Raffaele Ferrari ₃₃ , John E Landers ₈ , Adriano Chiò ₃₄ , J Raphael Gibbs ₂ , Clifton L Dalgard ₃₅ , Sonja W Scholz ₃₆ , Bryan J Traynor ₃₇

Affiliation

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA; Research and Development Service, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA; Department of Veterans Affairs Medical Center, Bedford, MA 01730, USA.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK.
Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, Lund 221 84, Sweden.
Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, Lund 221 84, Sweden; Department of Internal Medicine, Sahlgrenska Academy, University of Gottenburg, Gottenburg 413 45, Sweden.
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden.
Cambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge Biomedical Campus, Cambridge CB2 02Z, UK.
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy; MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
Department of Neurology, Royal Free Hospital, London NW3 2PF, UK; Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Department of Anatomy, Physiology and Genetics, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
Department of Neurology - Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan 20122, Italy.
Department of Neuroscience & Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 3JH, UK.
The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
Longitudinal Studies Section, National Institute on Aging, Baltimore, MD 21224, USA.
Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, USA.
Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK.
Department of Neurology & Program in Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA; Research and Development Service, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA.
Department of Neurology, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA; Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA.
Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; NINR University College London Hospitals Biomedical Research Centre, University College London, London W1T 7DN, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Neurology, Royal Free Hospital, London NW3 2PF, UK.
Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin 10126, Italy; Institute of Cognitive Sciences and Technologies, C.N.R., Rome 00185, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin 10126, Italy.
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA.

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.

中文翻译：

额颞叶痴呆和肌萎缩侧索硬化症患者的致病性亨廷顿蛋白重复扩增

我们通过分析 2,442 名 FTD/ALS 患者、2,599 名路易体痴呆 (LBD) 患者和 3,158 名神经健康患者的全基因组序列数据，研究了重复扩增在额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS) 发病机制中的作用。科目。在三名 (0.12%) 诊断为纯 FTD/ALS 综合征的患者中发现了亨廷顿 ( HTT ) 基因的致病性扩展（范围，40-64 个 CAG 重复序列），但在 LBD 或健康队列中不存在。我们在 3,674 名 FTD/ALS 患者的独立样本中重复了我们的研究结果。对两名患者的尸检评估揭示了 FTD/ALS 的经典 TDP-43 病理学，以及额叶皮层中亨廷顿蛋白阳性、泛素阳性聚集体。两种病例均不存在病理学上定义的亨廷顿病的新纹状体萎缩。我们的研究结果揭示了HTT重复扩展与 FTD/ALS 综合征之间的病因学关系，并表明应考虑对 FTD/ALS 患者进行HTT重复扩展基因筛查。

更新日期：2021-02-03

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>