The long term objectives of this grant are to understand the biological function of type VI collagen and to determine its role in disease processes. Type VI collagen, a heterotrimer of alpha1(VI), alpha2(VI) and alpha3(VI) chains, is the major component of beaded microfibrils found in almost all tissues. Changes in the expression or distribution of type VI collagen have been described in many pathological conditions, including fibrosis, diabetes, and osteoarthritis. Recently, mutations in type VI collagen genes have been found in a dominantly inherited, childhood onset genetic disorder, Bethlem myopathy. Under the auspices of this grant, we have defined the protein and gene structures for the three chains of human type VI collagen, delineated their binding interactions and expression patterns, and identified gene mutations in patients with Bethlelm myopathy. In this renewal application, the major focuses are to define the molecular and pathological mechanisms underlying type VI collagen gene mutations in Bethlem myopathy, and to examine in greater detail the role of type VI collagen in myogenesis.
The specific aims are: (1) To define additional mutations in type VI collagen genes that cause Bethlem myopathy, and to examine how mutations in type VI collagen genes affect its biosynthesis, secretion, and microfibril assembly in dermal fibroblasts from affected individuals. (2) To study the role of type VI collagen in myogensis using in vitro differentiation models and to examine the interactions of type VI collagen with muscle proteins. (3) To generate transgenic mice with mutations in type VI collagen by gene targeting and to analyze the phenotypes of the mice with a focus on the development of skeletal muscle. These studies will lead to future development of diagnostic tests and therapeutic treatment for Bethlem myopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR038912-16
Application #
6511688
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Tyree, Bernadette
Project Start
1987-07-15
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
16
Fiscal Year
2002
Total Cost
$316,230
Indirect Cost
Name
Thomas Jefferson University
Department
Dermatology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Pepe, Guglielmina; Lucarini, Laura; Zhang, Rui-Zhu et al. (2006) COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy. Ann Neurol 59:190-5
Lucarini, Laura; Giusti, Betti; Zhang, Rui-Zhu et al. (2005) A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy. Hum Genet 117:460-6
Lucioli, S; Giusti, B; Mercuri, E et al. (2005) Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 64:1931-7
Lampe, A K; Dunn, D M; von Niederhausern, A C et al. (2005) Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet 42:108-20
Pan, Te-Cheng; Zhang, Rui-Zhu; Sudano, Dominick G et al. (2003) New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet 73:355-69
Zhang, Rui-Zhu; Sabatelli, Patrizia; Pan, Te-Cheng et al. (2002) Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy. J Biol Chem 277:43557-64
Pepe, Guglielmina; de Visser, Marianne; Bertini, Enrico et al. (2002) Bethlem myopathy (BETHLEM) 86th ENMC international workshop, 10-11 November 2000, Naarden, The Netherlands. Neuromuscul Disord 12:296-305
Dziadek, Marie; Kazenwadel, Janette S; Hendrey, Jaqueline A et al. (2002) Alternative splicing of transcripts for the alpha 3 chain of mouse collagen VI: identification of an abundant isoform lacking domains N7-N10 in mouse and human. Matrix Biol 21:227-41
Verrecchia, F; Chu, M L; Mauviel, A (2001) Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 276:17058-62
Camacho Vanegas, O; Bertini, E; Zhang, R Z et al. (2001) Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci U S A 98:7516-21

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