Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA.
Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA.
复制标题
DOI：
10.1371/journal.pgen.1010895
复制
发表时间：
2023-08
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
由核纤层蛋白基因 LMNA 错义突变引起的横纹肌纤层蛋白病的特征是心脏功能障碍，并且通常有骨骼肌缺陷。预测哪些 LMNA 变异具有致病性并了解其生理效应的尝试落后于变异发现。我们通过在 lmn-1 基因内的保守残基处引入致病性人类 LMNA 变异和意义未知的变异，创建了横纹肌核纤层蛋白病的秀丽隐杆线虫模型。严重的错义变异降低了秀丽隐杆线虫的生育力和/或运动能力。许多核纤层蛋白变异株的皮下细胞核中存在明显的核形态缺陷，表明核膜完整性丧失。横纹肌疾病涉及的两类错义突变的表型严重程度有所不同，但总体而言，与人类骨骼和心肌缺陷相关的变异在我们的模型中导致比预测单独破坏心脏功能的变异更严重的表型。我们还鉴定了功能分离等位基因 lmn-1(R204W)，它表现出正常的活力和游泳行为，但具有严重的核迁移缺陷。因此，我们建立了横纹肌核纤层蛋白病的线虫化身，并鉴定了 LMNA 变体，这些变体可以深入了解正常发育过程中的核纤层蛋白机制。肌营养不良症是一种进行性肌肉萎缩性疾病，最终导致心脏病。 LMNA 基因编码参与细胞核结构和组织的中间丝蛋白，其突变是导致这种疾病的常见原因，但人们对此知之甚少。人们对 LMNA 范围内的变异如何导致导致疾病的机制性细胞缺陷知之甚少，这给诊断疾病和开发治疗方法带来了障碍。我们发现，通过将 LMNA 引起的横纹肌疾病患者中发现的氨基酸替换引入线虫的保守 lmn-1 基因中，我们可以快速测试这些变体的功能，以更好地了解它们的作用。我们发现，模拟涉及人类骨骼和心肌的疾病的变体对秀丽隐杆线虫的致病性最强，通常会影响生存能力和运动，而那些单独模拟心脏病的变体对秀丽隐杆线虫的有害影响较小。因此，我们的新秀丽隐杆线虫模型可用于诊断和预测人类 LMNA 新变异的严重程度，并更好地了解正常发育中核纤层蛋白的分子机制。
Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lag behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development. Muscular dystrophy is a progressive muscle-wasting disorder that eventually leads to cardiac disease. Mutations in the LMNA gene, which encodes an intermediate filament protein involved in the structure and organization of the nucleus, is a common but poorly understood cause of this disease. How variants across the breadth of LMNA contribute to mechanistic cellular defects that lead to disease is poorly understood, leading to hurdles in diagnosing disease and developing treatments. We found that by introducing amino acid substitutions found in patients with striated muscle disorders caused by LMNA into the conserved lmn-1 gene of the nematode C. elegans, we could rapidly test the function of these variants to better understand their roles. We found that variants modeling diseases that involve both skeletal and cardiac muscle in humans were the most pathogenic in C. elegans, typically affecting both viability and movement, while those that modeled cardiac disease alone had less deleterious effects in C. elegans. Thus, our new C. elegans models can be used to diagnose and predict the severity of new variants of human LMNA as well as to better understand the molecular mechanisms of lamins in normal development.
登录
查看更多内容
影响因子：
4.4
作者：
Fidzianska, A;Hausmanowa-Petrusewicz, I
通讯作者：
Hausmanowa-Petrusewicz, I
影响因子：
3.3
作者：
Bank EM;Ben-Harush K;Wiesel-Motiuk N;Barkan R;Feinstein N;Lotan O;Medalia O;Gruenbaum Y
通讯作者：
Gruenbaum Y
DOI：
10.1016/s0735-1097(02)01724-2
发表时间：
2002-03-20
影响因子：
24
作者：
Arbustini, E;Pilotto, A;Tavazzi, L
通讯作者：
Tavazzi, L
影响因子：
3.5
作者：
Dalin, Martin G.;Engstrom, Par G.;Bergo, Martin O.
通讯作者：
Bergo, Martin O.
影响因子：
20.1
作者：
Chandar, Suchitra;Yeo, Li Sze;Fatkin, Diane
通讯作者：
Fatkin, Diane