Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study

使用下一代测序揭示散发性包涵体肌炎的发病机制 - 国际 IBM 联盟遗传学研究

基本信息

  • 批准号:
    MR/J004758/1
  • 负责人:
  • 金额:
    $ 88.08万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2013
  • 资助国家:
    英国
  • 起止时间:
    2013 至 无数据
  • 项目状态:
    已结题

项目摘要

The commonest muscle disease that occurs in patients over the age of 45 years is a muscle wasting disease called inclusion body myositis (IBM). Patients typically develop progressive muscle wasting and weakness that progresses and causes marked disability and ultimately death from immobility over the course of around 10 years. There are no effective treatment for patients with IBM. The precise cause of this muscle disease is not known. However, on muscle biopsies from patients there seems to be a combination of some mild inflammation in the muscle and also an accumulation of abnormal proteins, similar to the accumulated proteins that are seen in the brains of patients with neurodegenerative diseases such as Alzheimer's, fronto-temporal dementia and motor neurone disease. Previous research has indicated that there may be genetic factors that predispose people to getting IBM but the previous studies have been quite small and not conclusive. In this research we have brought together experts in IBM from all over the world including Europe, USA and Australia to generate increased awareness of IBM, define diagnostic criteria, collect clinical information and DNA. Over the last three years we have been able to collect the largest group ever of IBM patients and DNA samples - approximately 950 cases and this number will be over 1000 once this study begins. The patient DNA and muscle tissue has been carefully stored for this work. This very large collection of DNA has put us in a very good position to undertake much more detailed genetic studies than have ever been done before to try and work out what the genetic risks factors and genes are that predispose people to this devastating disease.We plan to use the latest next generation sequencing techniques to unravel all the coding variants (those that alter proteins) that are present in 200 IBM patients DNA samples in comparison with 200 patients that are controls with normal muscles. We will analyze the DNA that we have already extracted from patients muscle tissue as this is the best diagnostic group. We will replicate the variants found in a further 700 IBM cases and over 2200 other controls. We are highly experienced in next generation sequencing technology and this has been strengthened by the recent award of a Wellcome Trust equipment grant to purchase the latest next generation sequencer. Recently we have used these techniques to identify the genetic causes of other neuromuscular disorders.In comparison with other disorders like Alzheimer's disease, where proteins are aggregated in the brain as opposed to the muscle as in IBM, the greatest advancement have been made with the identification of disease genes and genetic risk factors. If we can work out what the key genes are and how these disease causing pathways function, we will pave the way for new therapies and treatments to help patients.
45岁以上患者中最常见的肌肉疾病是一种肌肉萎缩疾病,称为包涵体肌炎(IBM)。患者通常会出现进行性肌肉萎缩和无力,并在大约10年的时间里逐渐恶化,导致明显的残疾,最终因动弹不得而死亡。目前还没有针对IBM患者的有效治疗方法。这种肌肉疾病的确切病因尚不清楚。然而,从患者的肌肉活检中发现,肌肉中似乎有一些轻微的炎症和异常蛋白质的积累,类似于阿尔茨海默氏症、额颞叶痴呆和运动神经元疾病等神经退行性疾病患者的大脑中所见的积累蛋白质。以前的研究表明,可能有遗传因素使人们容易得IBM,但以前的研究规模很小,没有定论。在这项研究中,我们汇集了来自世界各地的IBM专家,包括欧洲、美国和澳大利亚,以提高对IBM的认识,定义诊断标准,收集临床信息和DNA。在过去的三年里,我们已经能够收集到有史以来最大的IBM患者和DNA样本——大约950例,一旦这项研究开始,这个数字将超过1000。为了这项工作,病人的DNA和肌肉组织都被小心地保存了起来。大量的DNA收集使我们处于一个非常有利的位置,可以进行比以往任何时候都更详细的基因研究,试图找出哪些遗传风险因素和基因使人们容易患上这种毁灭性的疾病。我们计划使用最新的下一代测序技术来解开200名IBM患者DNA样本中存在的所有编码变体(改变蛋白质的那些),并将其与200名正常肌肉对照的患者进行比较。我们将分析从患者肌肉组织中提取的DNA,因为这是最好的诊断组。我们将复制在另外700个IBM案例和2200多个其他控制中发现的变体。我们在下一代测序技术方面经验丰富,最近获得了惠康信托基金的设备赠款,以购买最新的下一代测序仪,这一点得到了加强。最近,我们已经使用这些技术来确定其他神经肌肉疾病的遗传原因。与其他疾病(如阿尔茨海默病,蛋白质聚集在大脑中,而不是像IBM那样聚集在肌肉中)相比,最大的进步是识别疾病基因和遗传风险因素。如果我们能弄清楚关键基因是什么,以及这些致病途径是如何起作用的,我们将为新的疗法和治疗方法铺平道路,以帮助患者。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alpha-synuclein mRNA expression in oligodendrocytes in MSA.
  • DOI:
    10.1002/glia.22653
  • 发表时间:
    2014-06
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Asi, Yasmine T.;Simpson, Julie E.;Heath, Paul R.;Wharton, Stephen B.;Lees, Andrew J.;Revesz, Tamas;Houlden, Henry;Holton, Janice L.
  • 通讯作者:
    Holton, Janice L.
Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.
Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.
  • DOI:
    10.1038/s41380-019-0410-8
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    11
  • 作者:
    Arber C;Toombs J;Lovejoy C;Ryan NS;Paterson RW;Willumsen N;Gkanatsiou E;Portelius E;Blennow K;Heslegrave A;Schott JM;Hardy J;Lashley T;Fox NC;Zetterberg H;Wray S
  • 通讯作者:
    Wray S
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Henry Houlden其他文献

Rare disease gene association discovery in the 100,000 Genomes Project
10 万基因组计划中的罕见病基因关联发现
  • DOI:
    10.1038/s41586-025-08623-w
  • 发表时间:
    2025-02-26
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Valentina Cipriani;Letizia Vestito;Emma F. Magavern;Julius O. B. Jacobsen;Gavin Arno;Elijah R. Behr;Katherine A. Benson;Marta Bertoli;Detlef Bockenhauer;Michael R. Bowl;Kate Burley;Li F. Chan;Patrick Chinnery;Peter J. Conlon;Marcos A. Costa;Alice E. Davidson;Sally J. Dawson;Elhussein A. E. Elhassan;Sarah E. Flanagan;Marta Futema;Daniel P. Gale;Sonia García-Ruiz;Cecilia Gonzalez Corcia;Helen R. Griffin;Sophie Hambleton;Amy R. Hicks;Henry Houlden;Richard S. Houlston;Sarah A. Howles;Robert Kleta;Iris Lekkerkerker;Siying Lin;Petra Liskova;Hannah H. Mitchison;Heba Morsy;Andrew D. Mumford;William G. Newman;Ruxandra Neatu;Edel A. O’Toole;Albert C. M. Ong;Alistair T. Pagnamenta;Shamima Rahman;Neil Rajan;Peter N. Robinson;Mina Ryten;Omid Sadeghi-Alavijeh;John A. Sayer;Claire L. Shovlin;Jenny C. Taylor;Omri Teltsh;Ian Tomlinson;Arianna Tucci;Clare Turnbull;Albertien M. van Eerde;James S. Ware;Laura M. Watts;Andrew R. Webster;Sarah K. Westbury;Sean L. Zheng;Mark Caulfield;Damian Smedley
  • 通讯作者:
    Damian Smedley
Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis
由新型非编码重复扩增引起的神经系统疾病:临床特征和鉴别诊断
  • DOI:
    10.1016/s1474-4422(24)00167-4
  • 发表时间:
    2024-07-01
  • 期刊:
  • 影响因子:
    45.500
  • 作者:
    Elisa Vegezzi;Hiroyuki Ishiura;D Cristopher Bragg;David Pellerin;Francesca Magrinelli;Riccardo Currò;Stefano Facchini;Arianna Tucci;John Hardy;Nutan Sharma;Matt C Danzi;Stephan Zuchner;Bernard Brais;Mary M Reilly;Shoji Tsuji;Henry Houlden;Andrea Cortese
  • 通讯作者:
    Andrea Cortese
Tissue-specific emTCF4/em triplet repeat instability revealed by optical genome mapping
通过光基因组图谱揭示组织特异性 emTCF4/em 三核苷酸重复不稳定性
  • DOI:
    10.1016/j.ebiom.2024.105328
  • 发表时间:
    2024-10-01
  • 期刊:
  • 影响因子:
    10.800
  • 作者:
    Christina Zarouchlioti;Stephanie Efthymiou;Stefano Facchini;Natalia Dominik;Nihar Bhattacharyya;Siyin Liu;Marcos Abreu Costa;Anita Szabo;Amanda N. Sadan;Albert S. Jun;Enrico Bugiardini;Henry Houlden;Andrea Cortese;Pavlina Skalicka;Lubica Dudakova;Kirithika Muthusamy;Michael E. Cheetham;Alison J. Hardcastle;Petra Liskova;Stephen J. Tuft;Alice E. Davidson
  • 通讯作者:
    Alice E. Davidson
Homozygous variants in emWDR83OS/em lead to a neurodevelopmental disorder with hypercholanemia
emWDR83OS/em 中的纯合变异导致伴有高胆血症的神经发育障碍
  • DOI:
    10.1016/j.ajhg.2024.10.002
  • 发表时间:
    2024-11-07
  • 期刊:
  • 影响因子:
    8.100
  • 作者:
    Scott Barish;Sheng-Jia Lin;Reza Maroofian;Alper Gezdirici;Hamoud Alhebby;Aurélien Trimouille;Marta Biderman Waberski;Tadahiro Mitani;Ilka Huber;Kristian Tveten;Øystein L. Holla;Øyvind L. Busk;Henry Houlden;Ehsan Ghayoor Karimiani;Mehran Beiraghi Toosi;Reza Shervin Badv;Paria Najarzadeh Torbati;Fatemeh Eghbal;Javad Akhondian;Ayat Al Safar;Davut Pehlivan
  • 通讯作者:
    Davut Pehlivan
Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production
  • DOI:
    10.1007/s00018-025-05612-0
  • 发表时间:
    2025-02-07
  • 期刊:
  • 影响因子:
    6.200
  • 作者:
    Nafisa R. Komilova;Plamena R. Angelova;Elisa Cali;Annarita Scardamaglia;Ulugbek Z. Mirkhodjaev;Henry Houlden;Noemi Esteras;Andrey Y. Abramov
  • 通讯作者:
    Andrey Y. Abramov

Henry Houlden的其他文献

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{{ truncateString('Henry Houlden', 18)}}的其他基金

Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders
利用基因组学和转录组学的力量彻底改变神经系统疾病的诊断和理解
  • 批准号:
    MR/S01165X/1
  • 财政年份:
    2019
  • 资助金额:
    $ 88.08万
  • 项目类别:
    Research Grant
Genetic Dissection of Neuromuscular Disorders
神经肌肉疾病的基因剖析
  • 批准号:
    G1001253/1
  • 财政年份:
    2011
  • 资助金额:
    $ 88.08万
  • 项目类别:
    Research Grant
The Genetics and Pathophysiology of Spinocerebellar Degeneration
脊髓小脑变性的遗传学和病理生理学
  • 批准号:
    G0802760/1
  • 财政年份:
    2010
  • 资助金额:
    $ 88.08万
  • 项目类别:
    Fellowship
Investigation of the Pathophysiology of Spinocerebellar Degeneration
脊髓小脑变性的病理生理学研究
  • 批准号:
    G108/638/1
  • 财政年份:
    2006
  • 资助金额:
    $ 88.08万
  • 项目类别:
    Fellowship

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