Genetic basis of myopathy with Paget disease of bone

佩吉特骨病肌病的遗传基础

• 批准号: 7478112
• 负责人: VIRGINIA Eunice KIMONIS
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478112
• 关键词: ATP phosphohydrolase; Address; Affect; Binding; Biochemical; Biopsy; Bone Diseases; Brain; Cell Line; Cell physiology; Cellular Stress; Chromosomes; Chromosomes, Human, Pair 9; Clinical; Collaborations; Condition; Dementia; Development; Diagnosis; Disease; Distal; Ethical Issues; Family; Frontotemporal Dementia; Genes; Genetic; Genetic Counseling; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Inclusion Bodies; Individual; Inherited; Limb structure; Limb-Girdle Muscular Dystrophies; Link; Messenger RNA; Molecular; Muscle; Muscle Weakness; Muscular Dystrophies; Mutate; Mutation; Mutation Analysis; Myopathy; Nature; Osteitis Deformans; Osteogenesis; Paget' s Disease; Participant; Pathway interactions; Patients; Polyubiquitin; Primary Lateral Sclerosis; Proteins; Publishing; Purpose; Recruitment Activity; Research; Research Project Grants; Research Subjects; Role; Sampling; Screening procedure; Skeletal Muscle; Stress; Testing; Tissues; Transgenic Mice; Western Blotting; base; member; mouse model; protein expression; protein protein interaction; research clinical testing; transmission process; valosin-containing protein

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.

描述（由申请人提供）：遗传性包涵体肌病（h-IBM）是一组遗传多样性疾病，其特征为远端/近端肢带肌无力和肌肉中存在包涵体。我们最近发现了这组疾病的一个新成员[1，2;附件]，其中包涵体肌病与骨佩吉特病（PDB）和/或额颞叶痴呆（FTD）相关。这种新的疾病以前诊断为各种疾病，如肢带型肌营养不良症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，通常在30 - 40岁发病，并与早期死亡有关。我们已经鉴定出IBMPFD中的基因VCP（含缬氨肽蛋白）突变。该研究项目的目的是：1。佩吉特骨病相关肌病（IBMPFD）家族的临床和分子研究：招募新的IBMPFD家族进行临床评价、生化、放射学和分子（DNA）检测。收集IBMPFD家系的尸检和活检组织进行组织学和生化研究。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小鼠模型的开发：开发两个转基因小鼠系;一个过表达常见VCP突变（R155 H），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途径和相互作用蛋白：表征VCP中鉴定的突变性质的基础体外研究（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）。研究分化期间和应激条件下C2 C12细胞系（稳定转染的wt和R155 H VCP）中的VCP特异性途径。

项目成果

Global gene expression profiling in R155H knock-in murine model of VCP disease.

• DOI: 10.1111/cts.12241
• 发表时间: 2015-02
• 期刊: Clinical and translational science
• 作者: Nalbandian A;Ghimbovschi S;Wang Z;Knoblach S;Llewellyn KJ;Vesa J;Hoffman EP;Kimonis VE
• 通讯作者: Kimonis VE

Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.

• DOI: 10.1093/hmg/ddaa248
• 发表时间: 2020-12
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Lan Weiss;K. Jung;A. Nalbandian;K. Llewellyn;Howard Yu;Lac Ta;I. Chang;M. Migliore;Erica Squire;Faizy Ahmed;D. Piomelli;V. Kimonis

Early-onset Alzheimers and cortical vision impairment in a woman with valosin-containing protein disease associated with 2 APOE ε4/APOE ε4 genotype.

患有与 2 APOE ε4/APOE ε4 基因型相关的含缬洛辛蛋白疾病的女性的早发性阿尔茨海默病和皮质视力障碍。

• DOI: 10.1097/wad.0b013e318298e54f
• 发表时间: 2015
• 期刊: Alzheimer disease and associated disorders
• 影响因子: 2.1
• 作者: Shamirian,Sharis;Nalbandian,Angèle;Khare,Manaswitha;Castellani,Rudolph;Kim,Ronald;Kimonis,VirginiaE
• 通讯作者: Kimonis,VirginiaE

Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia.

预测性基因检测对 VCP 包涵体肌病、佩吉特骨病和额颞叶痴呆的心理影响。

• DOI: 10.1007/s10897-015-9819-7
• 发表时间: 2015
• 期刊: Journal of genetic counseling
• 影响因子: 1.9
• 作者: Surampalli,Abhilasha;Khare,Manaswitha;Kubrussi,Georgette;Wencel,Marie;Tanaja,Jasmin;Donkervoort,Sandra;Osann,Kathryn;Simon,Mariella;Wallace,Douglas;Smith,Charles;MMcInerney-Leo,Aideen;Kimonis,Virginia
• 通讯作者: Kimonis,Virginia