The Multiple Faces of Valosin-Containing Protein-Associated Diseases: Inclusion Body Myopathy with Paget's Disease of Bone, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis
The Multiple Faces of Valosin-Containing Protein-Associated Diseases: Inclusion Body Myopathy with Paget's Disease of Bone, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis
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DOI：
10.1007/s12031-011-9627-y
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发表时间：
2011-11-01
影响因子：
3.1
通讯作者：
Kimonis, Virginia E.
中科院分区：
文献类型：
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作者：
Nalbandian, Angele;Donkervoort, Sandra;Kimonis, Virginia E.
与骨佩吉特病和额颞叶痴呆 (IBMPFD) 相关的包涵体肌病是一种外显率可变的进行性致命遗传性疾病，主要影响三种主要组织类型：肌肉 (IBM)、骨 (PDB) 和脑 (FTD)。 IBMPFD 是由普遍表达的含缬洛辛蛋白 (VCP) 基因的突变引起的，VCP 基因是 AAA-ATPase 超家族的成员。大多数 IBM 患者都有进行性近端肌无力。免疫组织化学显示，肌肉活检显示泛素和 TAR DNA 结合蛋白 43 (TDP-43) 阳性的边缘空泡和内含物。 PDB 在一半的个体中可见，是由过度活跃的破骨细胞引起的，临床上与疼痛、血清碱性磷酸酶升高以及粗小梁和硬化病变的 X 射线发现有关。三分之一的人在平均 55 岁被诊断出 FTD，其临床特征为理解能力缺陷、记忆障碍、计算障碍和社交意识缺失。大脑中也发现了泛素和 TDP-43 阳性神经元包涵体。基因型-表型相关性很难观察到明显的家族内和家族间变异。家族内的不同表型包括额颞叶痴呆、肌萎缩侧索硬化症、帕金森病、肌强直、白内障和肛门功能不全等。细胞和动物模型表明 IBMPFD 组织存在病理紊乱，包括蛋白质降解改变、自噬途径改变、细胞凋亡和线粒体功能障碍。目前，携带 VCP 突变的小鼠和果蝇模型提供了对人类 IBMPFD 病理学的深入了解，并且可用作临床前研究和治疗策略测试的工具。在这篇综述中，我们将探讨VCP突变引起的IBMPFD的发病机制和临床表型。
Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype-phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.