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揭示儿童罕见神经系统疾病的分子原因
诸平
据英国伦敦帝国理工学院(Imperial College London)2023年11月18日提供的消息,一项由英国、伊朗、德国、美国、沙特阿拉伯、巴基斯坦、伊拉克、以色列、荷兰、意大利、埃及、奥地利、荷兰、塔吉克斯坦、土耳其、加拿大、泰国、孟加拉、巴基斯坦、巴西以及葡萄牙研究人员参与的新研究发现了儿童复杂的发育性大脑疾病背后的分子缺陷(Molecular causes of rare neurological condition in children revealed )。
由伦敦大学学院(UCL)领导、包括伦敦帝国理工学院研究人员在内的研究小组研究了一种称为酰基辅酶A结合域的蛋白6(acyl-CoA-binding domain-containing protein 6简称ACBD6)的特定调节蛋白在大脑中的作用。到目前为止,这种蛋白质缺陷的影响尚不清楚,但新研究发现的证据表明 ACBD6在维持健康的神经系统中发挥着重要作用。相关研究结果于2023年11月10日已经在《大脑》(Brain)杂志网站发表——Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, Kevin Huang, Tracy Lau, Cassidy Petree, Stephanie Efthymiou, Ehsan Ghayoor Karimiani, Maja Hempel, Elizabeth A Normand, Sabine Rudnik-Schöneborn, Ulrich A Schatz, Marc P Baggelaar, Muhammad Ilyas, Tipu Sultan, Javeria Raza Alvi, Manizha Ganieva, Ben Fowler, Ruxandra Aanicai, Gulsen Akay Tayfun, Abdulaziz Al Saman, Abdulrahman Alswaid, Nafise Amiri, Nilufar Asilova, Vorasuk Shotelersuk, Patra Yeetong, Matloob Azam, Meisam Babaei, Gholamreza Bahrami Monajemi, Pouria Mohammadi, Saeed Samie, Selina Husna Banu, Jorge Pinto Basto, Fanny Kortüm, Mislen Bauer, Peter Bauer, Christian Beetz, Masoud Garshasbi, Awatif Hameed Issa, Wafaa Eyaid, Hind Ahmed, Narges Hashemi, Kazem Hassanpour, Isabella Herman, Sherozjon Ibrohimov, Ban A Abdul-Majeed, Maria Imdad, Maksudjon Isrofilov, Qassem Kaiyal, Suliman Khan, Brian Kirmse, Janet Koster, Charles Marques Lourenço, Tadahiro Mitani, Oana Moldovan, David Murphy, Maryam Najafi, Davut Pehlivan, Maria Eugenia Rocha, Vincenzo Salpietro, Miriam Schmidts, Adel Shalata, Mohammad Mahroum, Jawabreh Kassem Talbeya, Robert W Taylor, Dayana Vazquez, Annalisa Vetro, Hans R Waterham, Mashaya Zaman, Tina A Schrader, Wendy K Chung, Renzo Guerrini, James R Lupski, Joseph Gleeson, Mohnish Suri, Yalda Jamshidi, Kailash P Bhatia, Barbara Vona, Michael Schrader, Mariasavina Severino, Matthew Guille, Edward W Tate, Gaurav K Varshney, Henry Houlden, Reza Maroofian. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain, 2023, awad380, DOI: 10.1093/brain/awad380. Published: 10 November 2023. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad380/7407365
参与此项研究的有来自英国伦敦大学学院神经病学研究所(UCL Institute of Neurology, London, UK)、英国伦敦帝国理工学院分子科学研究中心 (Imperial College London, Molecular Sciences Research Hub, London, UK)、英国弗朗西斯克里克研究所(The Francis Crick Institute, London, UK)、英国朴茨茅斯23大学(University of 23 Portsmouth, PO1 2DT, UK)、英国伦敦圣乔治大学(St George's University of London, London, UK)、英国纽卡斯尔大学(Newcastle University, Newcastle upon Tyne, NE2 4HH, UK)、英国泰恩河畔纽卡斯尔医院NHS基金会信托(Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK)、英国埃克塞特大学(University of Exeter, EX4 4QD, Exeter, UK)、英国诺丁汉大学医院NHS信托(Nottingham University Hospitals NHS Trust, NG5 1PB, Nottingham, UK)、英国诺和诺德牛津研究中心(Novo Nordisk Research Centre Oxford, Oxford, UK);伊朗萨布泽瓦尔医科大学(Sabzevar University of Medical Sciences, Sabzevar, Iran)、伊朗下一代遗传综合诊所(Next Generation Genetic Polyclinic, Mashhad, Iran)、伊朗北呼罗珊医科大学(North Khorasan University of Medical Sciences, Bojnurd, Iran)、伊朗德黑兰帕尔斯医院(Pars Hospital, Tehran, Iran)、伊朗德黑兰医科大学(Tehran University of Medical Sciences, Tehran, Iran)、伊朗塔比亚特莫德雷斯大学(Tarbiat Modares University, Tehran, Iran)、伊朗马什哈德医科大学(Mashhad University of Medical Sciences, Mashhad, Iran);德国宾根的埃伯哈德·卡尔斯大学(Eberhard Karls University, Tübingen, Germany)、德国CENTOGENE有限责任公司(CENTOGENE GmbH, Rostock, Germany)、德国汉堡-埃彭多夫大学医学中心(University Medical Center Hamburg-Eppendorf, Hamburg, Germany)、德国海德堡大学医院人类遗传学研究所(Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany)、德国慕尼黑工业大学人类遗传学研究所(Institute of Human Genetics, Technical University of Munich, Germany)、德国弗莱堡大学(Freiburg University, Freiburg, Germany)、德国哥廷根大学医学中心(University Medical Center Göttingen, Göttingen, Germany);美国俄克拉荷马医学研究基金会(Oklahoma Medical Research Foundation, Oklahoma City, OK, USA)、美国马里兰州盖瑟斯堡的GeneDx(GeneDx, Gaithersburg, Maryland, USA)、美国尼克拉斯儿童医院(Nicklas Children's Hospital, Miami, Florida, FL, USA)、美国德克萨斯州休斯顿贝勒医学院(Baylor College of Medicine, Houston, TX, USA) 、美国德克萨斯儿童医院(Texas Children's Hospital, Houston, TX, USA)、美国男孩镇国家研究医院(Boys Town National Research Hospital, Boys Town, NE, USA)、美国密西西比大学医学中心(University of Mississippi Medical Center, MS, USA)、美国哥伦比亚大学欧文医学中心(Columbia University Irving Medical Center, New York, USA)、美国德克萨斯州休斯顿贝勒医学院(Baylor College of Medicine, Houston, Texas, USA)、美国加州大学圣地亚哥分校(University of California, San Diego, La Jolla, CA, USA)、美国加州圣地亚哥雷迪儿童基因组医学研究所(Rady Children's Institute for Genomic Medicine, San Diego, CA, USA)、沙特阿拉伯国家神经科学研究所(National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia)、沙特阿拉伯沙特国王本·阿卜杜勒阿齐兹健康科学大学(King Saud Bin Abdulaziz University For Health Sciences, Riyadh, Saudi Arabia)、沙特阿拉伯利雅得国民警卫队卫生事务部{Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia} ;巴基斯坦斯瓦特的工程与应用科学大学(University of Engineering and Applied Sciences, Swat, Pakistan)、巴基斯坦伊斯兰学院大学(Islamia College University, Peshawar, Pakistan)、巴基斯坦拉合尔儿童医院儿童保健研究所(Institute of Child Health, Children Hospital, Lahore, Pakistan)、巴基斯坦华坎特的华医学院(Wah Medical College, Wah Cantt, Pakistan);伊拉克巴士拉大学(University of Basrah, Basrah, Iraq)、伊拉克巴格达先锋分子病理学实验室(The Pioneer Molecular Pathology Lab, Baghdad, Iraq);以色列海法克莱特医疗保健公司(Clalit Health Care, Haifa, Israel)、以色列海法西蒙·温特人类遗传学研究所(Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, Haifa, Israel)、以色列海法以色列理工学院(Technion institution of Technology, Haifa, Israel)、以色列海法锡安医疗中心(The Bnai Zion Medical Center, Haifa, Israel);荷兰阿姆斯特丹大学医学中心(Amsterdam University Medical Centers location AMC, Amsterdam, The Netherlands)、荷兰内梅亨拉德堡大学医学中心(Radboud University Medical Center, Nijmegen, The Netherlands);意大利佛罗伦萨迈耶儿童医院IRCCS(Meyer Children's Hospital IRCCS, Florence, Italy)、意大利佛罗伦萨大学(University of Florence, Florence, Italy)、意大利热那亚IRCCS詹尼纳·加斯利尼研究所(IRCCS Istituto Giannina Gaslini, Genoa, Italy);埃及开罗国家研究中心人类遗传学和基因组研究所(Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt)、奥地利因斯布鲁克医科大学人类遗传学研究所(Institute of Human Genetics, Medical University Innsbruck, Austria)、荷兰乌得勒支大学(Utrecht University, 3584 CH Utrecht, The Netherlands)、塔吉克斯坦阿维森纳塔吉克斯坦国立医科大学(Avicenna Tajik State Medical University, Dushanbe, Tajikistan)、土耳其马尔马拉大学医学院(Marmara University Medical School, Istanbul, Turkey)、加拿大不列颠哥伦比亚大学(University of British Columbia, Vancouver, Canada)、泰国朱拉隆功大学(Chulalongkorn University, Bangkok, Thailand)、孟加拉Khan Shishu(儿童)医院和儿童保健研究所{Dr. M.R. Khan Shishu (Children) Hospital and Institute of Child health, Mirpur, Dhaka- 1216, Bangladesh}、巴基斯坦曼塞赫拉的哈扎拉大学(Hazara University, Mansehra, Pakistan)、巴西圣保罗里贝贝普雷图大学医学院(Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil)、葡萄牙北里斯本大学医院中心圣玛丽亚医院(Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal)的研究人员。
这项新研究揭示了ACBD6故障在一种极其罕见的儿童疾病——称为常染色体隐性 ACBD6 相关疾病(Autosomal Recessive ACBD6-related disorder)中的作用。其特点是认知和运动技能发展迟缓,并与肌张力障碍和帕金森症有关。这一发现是通过使用先进的基因组技术和广泛的全球数据共享而实现的,来自全球72家研究机构的89名临床医生和科学家参与了此项研究。
多方面的方法(Multifaceted approach)
对这种罕见疾病的了解始于对一种复杂神经系统疾病的研究,该疾病影响一个家庭的三个兄弟姐妹,他们的ACBD6基因发生突变。由于接下来几年的广泛国际合作,更多患有类似遗传性疾病的受影响家庭被发现,并且逐渐开始在受影响者的独特临床和放射学特征中出现相似之处。
研究人员采取了多方面的方法,调查了来自28个无关家庭的45名受影响个体,并将他们的研究扩展到包括动物模型。由英国帝国理工学院化学系 Ed Tate 教授领导的帝国理工学院团队负责研究 ACBD6 缺陷对一种特定类型的蛋白质修饰——N-豆蔻酰化( N-myristoylation)的影响。
来自弗朗西斯·克里克研究所(The Francis Crick Institute)和帝国理工学院化学系的Wouter Kallemeijn 博士说:“我们能够在ACBD6缺陷型青蛙和斑马鱼模型( frog and zebrafish models)中证实我们的患者发现,这些模型与人类ACBD6缺陷型患者具有非常相似的疾病症状-表明ACBD6在 N-豆蔻酰化中发挥重要作用,包括对神经发育和神经发育过程至关重要的蛋白质的作用。”
国际化努力(International endeavour)
伦敦大学学院神经病学研究所(UCL Queen Square Institute of Neurology)的共同主要作者Reza Maroofian博士说:“这项研究强调了系统调查相对大量的受超罕见疾病影响的明确定义的个体的未开发力量,并强调了我们可以从这些目前严重被忽视和资金不足的研究中了解多少人类生物学和病理学。这项国际努力证明了全球科学界的不懈奉献和集体专业知识,并凸显了不边缘化超罕见条件的至关重要性。”
伦敦大学学院神经病学研究所的共同主要作者Rauan Kaiyrzhanov博士说:“这项研究的直接影响是,将这些遗传性疾病引入医学界将有助于诊断全世界受这种疾病影响的家庭。
然而,这项研究的长期和更广泛的影响是,这种极其罕见的疾病,通常表现为异常运动,如肌张力障碍和帕金森病,可以帮助我们更好地理解人类这些疾病的生物学,并推进我们对与帕金森病和肌张力障碍等更常见的神经退行性运动疾病相关的生物学机制的认识。”
本研究得到了MRC (MRC:MR/S01165X/1, MR/S005021/1, G0601943, 3 MR/V012177/1)、英国国立卫生研究院伦敦大学学院医院生物医学研究中心,罗斯特里信托(The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK)、MSA的信任(MSA Trust)、英国大脑研究中心(Brain Research UK)、斯帕克斯GOSH慈善机构(Sparks GOSH Charity)、英国肌肉萎缩症协会(Muscular Dystrophy UK简称MDUK)、美国肌肉萎缩症协会(Muscular Dystrophy Association简称MDA USA)、英国应用生物学和生物科学研究理事会(Biotechnology and Biological Sciences Research Council简称BBSRC BB/N01541X/1, BB/T002255/1, 7BB/W015420/1, BB/R014841/1)、欧盟的地平线2020研究和创新计划(European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 812968 PERICO;grant agreement No 779257)、罗斯特里信托博士奖(Rosetrees Trust PhD Plus award: PhD2022\100042)、全球帕金森遗传计划{ Global Parkinson’s Genetic Program (GP2) MJFF Grant ID: MJFF-022153}、德国蒂宾根大学校内基金{ Intramural Funding (fortüne) at the University of Tübingen (2545-1-0)}、德国巴登-符腾堡州科学、研究和艺术部(Ministry of Science, Research and Art Baden-Württemberg)、德国研究基金会{ Deutsche Forschungsgemeinschaft简称DFG, / German Research Foundation VO 2138/7‐1 grant 469177153; Project-ID 22 431984000 – SFB 1453 (CRC Nephgen)}、欧盟委员会居里夫人个人奖学金{ European Commission (Marie Sklodowska Curie Individual Fellowship grant 752165}、英国工程与物理科学研究理事会{ EPSRC (Impact Acceleration Account grant PS1042)}、英国癌症研究基金会(Cancer Research UK: C29637/A21451 and C29637/A20183,FC001057 and FC001097)、英国医学研究理事会(UK Medical Research Council: FC001057, FC001097, MR/W019027/1)、惠康基金会(Wellcome Trust: FC001057, FC001097, 212942/Z/18/Z)、卓越计划CIBSS(Excellence Initiative CIBSS - EXC-2189 - Project ID 390939984)、2018年意大利托斯卡纳地区健康呼吁{Tuscany Region Call for Health 2018 (grant DECODE24 EE)}、美国俄克拉荷马州医学研究基金会(Oklahoma Medical Research Foundation, USA)、美国国立卫生研究院{ US National Institutes of Health (NINDS 2 NS105078; NHGRI HG011758)}及痉挛截瘫基金会(Spastic Paraplegia Foundation)、惠康线粒体研究中心(Wellcome Centre for Mitochondrial Research: 203105/Z/16/Z)、英国线粒体疾病患者群{ Mitochondrial Disease Patient Cohort (UK) (G0800674)}、英国医学研究理事会国际神经肌肉疾病基因组医学中心(Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease: MR/S005021/1)、利利基金会(Lily Foundation)、泰国卫生系统研究所(Thailand’s Health Systems Research Institute HSRI 66-122)、新生命慈善补助金(Newlife Charity grant SG/18- 11 19/02)以及HEC-NRPU (HEC-NRPU grant 17341)的资助。
上述介绍,仅供参考。欲了解更多信息,敬请注意浏览原文或者相关报道。
The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
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