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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050236-05
Application #
7478112
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2004-08-15
Project End
2009-08-31
Budget Start
2008-07-01
Budget End
2009-08-31
Support Year
5
Fiscal Year
2008
Total Cost
$245,052
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Al-Obeidi, E; Al-Tahan, S; Surampalli, A et al. (2018) Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet 93:119-125
Nalbandian, Angèle; Ghimbovschi, Svetlana; Wang, Zuyi et al. (2015) Global gene expression profiling in R155H knock-in murine model of VCP disease. Clin Transl Sci 8:8-16
Surampalli, Abhilasha; Gold, Brian T; Smith, Charles et al. (2015) A case report comparing clinical, imaging and neuropsychological assessment findings in twins discordant for the VCP p.R155C mutation. Neuromuscul Disord 25:177-83
Surampalli, Abhilasha; Khare, Manaswitha; Kubrussi, Georgette et al. (2015) Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia. J Genet Couns 24:842-50
Shamirian, Sharis; Nalbandian, Angèle; Khare, Manaswitha et al. (2015) Early-onset Alzheimers and cortical vision impairment in a woman with valosin-containing protein disease associated with 2 APOE ?4/APOE ?4 genotype. Alzheimer Dis Assoc Disord 29:90-3
Nalbandian, Angèle; Llewellyn, Katrina J; Nguyen, Christopher et al. (2015) Targeted excision of VCP R155H mutation by Cre-LoxP technology as a promising therapeutic strategy for valosin-containing protein disease. Hum Gene Ther Methods 26:13-24
Dec, Eric; Rana, Prachi; Katheria, Veeral et al. (2014) Cytokine profiling in patients with VCP-associated disease. Clin Transl Sci 7:29-32
Nalbandian, Angèle; Llewellyn, Katrina J; Badadani, Mallikarjun et al. (2013) A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. Muscle Nerve 47:260-70
Mehta, S G; Khare, M; Ramani, R et al. (2013) Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia. Clin Genet 83:422-31
Nalbandian, Angèle; Ghimbovschi, Svetlana; Radom-Aizik, Shlomit et al. (2012) Global gene profiling of VCP-associated inclusion body myopathy. Clin Transl Sci 5:226-34

Showing the most recent 10 out of 26 publications