Genetic basis of myopathy with Paget disease of bone

描述(申请人提供)：遗传性包涵体肌病(h-IBM)是一组遗传多样性的疾病，其特征是四肢远端/近端的肌肉无力和肌肉中存在包涵体。我们最近发现了这组疾病中的一个新成员[1，2；附加]，其中包涵体肌病与Pagets病(PDB)和/或额颞部痴呆(FTD)相关。这种新的疾病以前被诊断为各种疾病，如四肢带状肌营养不良和肌萎缩侧索硬化症，已被归类为IBMPFD(MIM 605382)。包涵体肌病是进行性的，起病通常在30-40岁，并与早期死亡相关。我们在IBMPFD中发现了VCP(Valosin Containing Protein)基因的突变。建议研究项目的目的是：1.骨派杰氏病相关肌病家族的临床和分子研究(IBMPFD)：招募新的IBMPFD家系用于临床评估、生化、放射和分子(DNA)检测。收集IBMPFD家系的尸检和活检组织，用于组织学和生化研究。2.家族性HIBM和PDB中VCP的筛查：3.促进在遗传咨询环境中与参与研究的受试者分享VCP突变分析结果。4.IBMPFD小鼠模型的建立：建立两个高表达普通VCP突变(R155H)和高表达wt VCP的转基因小鼠系，并从临床和分子水平研究其表型变化。5.确定VCP途径和相互作用蛋白的特征：对VCP中已发现的突变的性质(即对ATPase活性、蛋白质-蛋白质相互作用和六聚体形成的影响)的基础体外研究。研究稳定表达VCP的C2C12细胞系(稳定表达的WT和R155H VCP)在分化和应激条件下的VCP特异性通路。

DESCRIPTION (provided by applicant): Hereditary inclusion body myopathies (h-IBM) are a genetically diverse group of disease characterized by distal/proximal limb-girdle muscle weakness and the presence of inclusion bodies in muscle. We recently identified a new member of this group of disorders [1,2; attached], in which the inclusion body myopathy is associated with Pagets disease of the bone (PDB) and/or frontotemporal dementia (FTD). This new disorder previously diagnosed as a variety of disorders such as limb girdle muscular dystrophy and amyotropic lateral sclerosis has been categorized as IBMPFD (MIM 605382). The inclusion body myopathy is progressive with onset typically in the 30s-40s and associated with early demise. We have identified the gene VCP (Valosin Containing Protein) as being mutated in IBMPFD. The aims of the proposed research project are: 1. Clinical and Molecular studies in families with myopathy associated with Paget disease of the bone (IBMPFD): Recruit new IBMPFD families for clinical evaluations, biochemical, radiological and molecular (DNA) testing. To collect post mortem and biopsy tissue from IBMPFD families for histological and biochemical studies. 2. Screening of VCP in familial HIBM and PDB: 3. Facilitate sharing of results of VCP mutation analysis in a genetic counseling setting with participating research subjects. 4. Development of a Mouse model of IBMPFD: To develop two transgenic mouse lines; one over expressing the common VCP mutation (R155H) and one over expressing wt VCP and study any phenotypic changes at the clinical and molecular level. 5. To characterize VCP pathways and interacting proteins: Basic in vitro studies to characterize the nature of mutations identified in VCP (i.e. effect on ATPase activity, protein-protein interactions, and hexamer formation). Study the VCP specific pathways in C2C12 cell lines (stably transfected wt and R155H VCP) during differentiation and under stress conditions.