Genetic basis of myopathy with Paget disease of bone

描述（由申请人提供）：遗传性包涵体肌病（h-IBM）是一种遗传多样性的疾病，其特征是远端/近端肢带肌无力和肌肉中包涵体的存在。我们最近发现了这类疾病的新成员[1,2；其中包涵体肌病与骨Pagets病（PDB）和/或额颞叶痴呆（FTD）相关。这种新的疾病以前被诊断为各种疾病，如肢体带状肌营养不良症和肌萎缩性侧索硬化症，已被归类为IBMPFD （MIM 605382）。包涵体肌病是进行性的，通常在30 -40岁发病，与早期死亡有关。我们已经确定基因VCP （Valosin Containing Protein）在IBMPFD中发生突变。拟建的研究项目的目的是：1。骨佩吉特病（IBMPFD）相关肌病家族的临床和分子研究：招募新的IBMPFD家族进行临床评估、生化、放射学和分子（DNA）检测。收集IBMPFD家族的死后和活检组织进行组织学和生化研究。2. 2 .家族性HIBM和PDB的VCP筛查：促进在遗传咨询环境中与参与研究的受试者分享VCP突变分析的结果。4. IBMPFD小鼠模型的建立：两个转基因小鼠系的建立一个过表达常见VCP突变（R155H），一个过表达wt VCP，并在临床和分子水平上研究任何表型变化。5. 表征VCP通路和相互作用蛋白：基本的体外研究表征VCP中确定的突变的性质（即对atp酶活性、蛋白质-蛋白质相互作用和六聚体形成的影响）。研究稳定转染了wt和R155H VCP的C2C12细胞系在分化和胁迫条件下的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.