The goal of this grant proposal is to elucidate the molecular mechanisms underlying the severe congenital muscular dystrophy type Ullrich (UCMD) and its milder counterpart Bethlem myopathy (BM). UCMD and BM combine features of muscular dystrophies and disorders of connective tissue resulting in significant weakness, progressive contractures, and joint laxity. Collagen VI is a microfibrillar component found in the extracellular matrix of most tissues, often in a pericellula r distribution . Its basic heterotrimeric unit is composed of three alpha chains. Mutations in the collagen VI genes (COL6A1, COL6A2, COL6A3) have been identified in BM and more recently also in UCMD. Althoug h BM usuall y is caused by dominan t mutations and UCMD by recessive mutations, we recently demonstrated dominan t negative mechanisms in UCMD also. The relevant functions of collagen VI are unclear, in various culture systems it has been shown to promote cell adhesion, differentiation , proliferation , and survival , whereas in a mouse model of Col6al inactivatio n there was evidence for increased apoptosis in the muscle. We hypothesize that fibroblasts are the primary cell type involved in UCMD and BM causing disease both in muscle (weakness) and in tendon (laxity and contractures) by producing an abnormal extracellular matrix (ECM). We further hypothesize that a specific disturbance of the interface between muscle and its extracellular matrix (ECM) leads to muscle apoptosis and weakness. In this project we will comprehensively characterize patients with UCMD and BM to define their clinical, morphological, and biochemical phenotypes and correlate these with the collagen VI genotypes. This will enable us to delineate the entire phenotypical, biochemical, and genetic spectrum of UCMD/BM. We wil l next determine changes in ECM gene expression as well as apoptosis in dermal fibroblasts cultures from the characterized patients with mutations in the collagen VI genes. Defining changes in ECM composition and fibroblast viability will allow us to understand the basis of the congenital and progressive contractures, the joint laxity, and to predict the nature of the abnormal ECM deposited in muscle. To study the molecular basis of the muscle weakness we are developing a novel co-culture system in which various patient derived fibroblast cultures supply an ECM for normal muscle cells. This system will be used to examine the effects of normal and mutant collagen VI matrices on the myotubes in culture. It will allow us to define the pathways that lead to muscle dysfunction and muscle cell death. Ultimately, we hope to understand the influence of ECM on the development of muscular dystrophy. Knowledge about these pathways is a prerequisite for developing effective treatment strategies in this new and important group of muscle disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051999-03
Application #
7258453
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$346,276
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Foley, A Reghan; Quijano-Roy, Susana; Collins, James et al. (2013) Natural history of pulmonary function in collagen VI-related myopathies. Brain 136:3625-33
Foley, A Reghan; Hu, Ying; Zou, Yaqun et al. (2011) Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy. Ann Neurol 69:206-11
Zhang, Rui-Zhu; Zou, Yaqun; Pan, Te-Cheng et al. (2010) Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant. J Biol Chem 285:10005-15
Collins, James; Bönnemann, Carsten G (2010) Congenital muscular dystrophies: toward molecular therapeutic interventions. Curr Neurol Neurosci Rep 10:83-91
Schessl, J; Columbus, A; Hu, Y et al. (2010) Familial reducing body myopathy with cytoplasmic bodies and rigid spine revisited: identification of a second LIM domain mutation in FHL1. Neuropediatrics 41:43-6
Foley, A Reghan; Hu, Ying; Zou, Yaqun et al. (2009) Autosomal recessive inheritance of classic Bethlem myopathy. Neuromuscul Disord 19:813-7
Schessl, Joachim; Taratuto, Ana L; Sewry, Caroline et al. (2009) Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1. Brain 132:452-64
Zou, Yaqun; Zhang, Rui-Zhu; Sabatelli, Patrizia et al. (2008) Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle: implications for congenital muscular dystrophy types Ullrich and Bethlem. J Neuropathol Exp Neurol 67:144-54
Pierson, T M; Zimmerman, R A; Tennekoon, G I et al. (2008) Mega-corpus callosum, polymicrogyria, and psychomotor retardation: confirmation of a syndromic entity. Neuropediatrics 39:123-7
Schessl, Joachim; Goemans, Nathalie M; Magold, Alexandra I et al. (2008) Predominant fiber atrophy and fiber type disproportion in early ullrich disease. Muscle Nerve 38:1184-91

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