中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (3): 575-576.doi: 10.4103/1673-5374.320986

• 观点:退行性病与再生 • 上一篇    下一篇

肌病和运动神经元变性中的 Matrin-3 功能障碍

  

  • 出版日期:2022-03-15 发布日期:2021-10-15

Matrin-3 dysfunction in myopathy and motor neuron degeneration

Caroline Ward, Udai Bhan Pandey*   

  1. Department of Pediatrics, Division of Child Neurology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA (Ward C, Pandey UB) 
    Department of Human Genetics, School of Public Health, School of Public Health, University of Pittsburgh; Center for Neuroscience Institute, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA (Pandey UB)
  • Online:2022-03-15 Published:2021-10-15
  • Contact: Udai Bhan Pandey, PhD, udai@pitt.edu.
  • Supported by:
    The present work was supported by the following funding sources: US National Institutes of Health (NIH), National Institute on Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA) R01 NS081303, R21 NS094921, R21 NS101661, R21 NS111768, R21 AG064940, R21 NS100055, Muscular Dystrophy Association, the ALS Association, and the Robert Packard Center for ALS at Johns Hopkins (to UBP). 

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摘要： Neural Regen Res：MATR3突变导致肌萎缩侧索硬化、额颞叶痴呆、和远端肌病
    MATR3中的常染色体显性Ser85Cys突变在一个多代家族中被发现，该家族表现为声带和咽部虚弱以及远端和不对称肌病。有趣的是，这些患者的神经生理学和肌肉活检结果显示了神经源性或肌病的模式。他们表现出一些标志性的上运动神经元损伤的征象，如“裂手”型、舌束状、冲击性下巴颤动和上肢反射。因此，对三个独立家庭的Ser85Cys患者进行了重新评估，发现他们在发病15年后出现进行性呼吸衰竭，导致死亡。这导致Ser85Cys相关疾病重新分类为“缓慢进行性肌萎缩侧索硬化伴远端肌病”，所有突变的频率约为0.5%。最初，3个队列包含与肌萎缩侧索硬化相关的错义MATR3突变；家族性肌萎缩侧索硬化患者中发现Phe115Cys（F115C）和Thr622Ala（T622A），散发性肌萎缩侧索硬化患者中发现Pro154s（P154S）。最新研究发现在一名出现额颞痴呆症状的患者中发现了被称为MATR3变体5的外显子15的重复。
    来自美国匹兹堡大学的Udai Bhan Pandey团队认为，MATR3引起神经肌肉退行性变的机制尚不清楚，目前怀疑MATR3突变相关的肌萎缩侧索硬化和其他远端肌病是多系统蛋白病的结果，包括RNA代谢失调。更具体地说，调节选择性剪接的RNA结合蛋白hnRNP可能是确定MATR3机制的关键，因为发现突变MATR3在果蝇中发挥毒性是必要的。MATR3的异位表达足以抑制与C9orf72扩张相关的神经退行性症状。在已知携带C9orf72重复序列扩增的肌萎缩侧索硬化患者中发现了MATR3阳性细胞质内含物，表明这两种形式的肌萎缩侧索硬化之间可能存在联系。MATR3与C9orf72中的G4C2结合，已发现MATR3识别的结合基序在散发性肌萎缩侧索硬化患者的选择性剪接盒外显子中富集。MATR3与G4C2 RNA病灶相互作用，并且通过MATR3的异位表达以RRM依赖的方式显著缓解体内G4C2相关的神经退行性变。虽然这是MATR3在G4C2重复RNA介导的神经退行性变中的一个新特点，但MATR3是否对C9orf72相关的肌萎缩侧索硬化有直接作用还有待观察。遗传模型的可用性对于揭示致病性突变的机制和遗传修饰以及开发模型疗法至关重要。果蝇的遗传模型让我们不仅发现了MATR3相关的肌萎缩侧索硬化，而且发现了肌萎缩侧索硬化的其他遗传原因，以及其他神经系统疾病。MATR3和基因修饰剂不仅已在果蝇模型中建立，而且在哺乳动物模型（如小鼠）中也已建立，为前瞻性的初级和临床前研究奠定了基础。基因模型的可用性增加不仅为未来的机制研究开辟了更多的途径，而且对于确定可能被开发用于治疗干预的生物途径也至关重要。
    文章在《中国神经再生研究（英文版）》杂志2022年 3 月  3 期发表。

https://orcid.org/0000-0002-6267-0179 (Udai Bhan Pandey) 

Abstract: The MATR3 protein was first identified comprising the nuclear matrix, an essential part of preserving the skeletal framework of the nucleus, amongst other nuclear matrins. Composed mainly of intrinsically disordered regions, the protein is made up of 847 amino acids, creating 4 distinct functional domains: two zinc-finger domains (ZF1 and ZF2) and two RNA-recognition motifs (RRM1 and RRM2,) as well as a highly acidic carboxy-terminal with histone-binding ability. This structural design allows MATR3 protein to interact with DNA and/or DNA/RNA-binding proteins, aiding in chromosomal and genomic integrity regulation, RNA-binding mediated post-transcriptional mRNA regulation, and nuclear lamina association to maintain nuclear framework. An autosomal dominant Ser85Cys (S85C) mutation in MATR3 was identified in a multigenerational family displaying vocal cord and pharyngeal weakness as well as distal and asymmetrical myopathy (Senderek et al., 2009). Intriguingly, a neurogenic or myopathic pattern was indicated by these patients neurophysiological and muscle biopsy-based examinations. They displayed several signs emblematic of upper motor neuron lesions such as a “split-hand” pattern, tongue fasciculations, brunt jaw-jerk, upper limb reflexes, and brisk knee. Due to this, S85C patients in three independent families were reassessed and found to suffer progressive respiratory failure leading to death 15 years after onset (Johnson et al., 2014), in contrast to the typical 2–5 years. This led to a recategorization of S85C-associated disorder to “slow progressive amytrophic lateral sclerosis (ALS) with distal myopathy,” and is approximated at 0.5% frequency of all mutations. Initially, 3 cohorts containing unique missense MATR3 mutations associated with ALS were characterized; Phe115Cys (F115C) and Thr622Ala (T622A) were found in familial ALS patients, and Pro154Ser (P154S) in a sporadic ALS patient (Johnson et al., 2014). Subsequently, 3 additional MATR3 mutations including p.Ser610Phe (Xu et al., 2016), a missense mutation found in ALS patients from Chinese origin with 3 variants (p.Ala313Gly, p.Arg147Lys, and p.Gln347Lys). Secondly, a duplication of exon 15 referred to as MATR3 Variant 5 (Castro et al., 2020) was found in a patient presenting symptoms of frontotemporal dementia, lastly, a heterozygous missense mutation called Ala72Thr was found in a Taiwanese ALS patient (Lin et al., 2015).