Abstract
BackgroundCollagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts.Aims & MethodsIn order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays.FindingsWe found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases.
Highlights
Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in collagen VI genes (COL6A1, COL6A2 and COL6A3) and is characterised by congenital hypotonia, proximal muscle weakness and distal joint hyperlaxity
Expression of collagen VI mRNA has been shown to increase in the early phases of wound healing and in keloids [6] as well as in other fibrotic processes such as systemic sclerosis [7] suggesting a role in matrix reorganisation, fibrosis and scaring in general
Collagen VI is abundant in the extracellular matrix of many tissues, where it binds to cell-surface receptors, integrins [9] and NG2 [10] and to other extracellular matrix (ECM) components including fibrillar collagens, collagen IV and fibronectin
Summary
Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in collagen VI genes (COL6A1, COL6A2 and COL6A3) and is characterised by congenital hypotonia, proximal muscle weakness and distal joint hyperlaxity. Multiple joint contractures and progressive respiratory insufficiency develop over time [1,2] In addition to these skeletal features, UCMD patients show a recognisable skin pathology in the form of follicular hyperkeratosis pilaris and abnormal scarring following skin injury mainly in the form of hypertrophic scars and keloids [3,4]. These constitute a fibrotic process due to the excessive deposition of collagen and other extracellular matrix proteins during the wound healing process [5] and can cause pain and pruritus and significant discomfort in patients that require frequent surgical interventions. Collagen VI in skeletal muscle and skin is produced by fibroblasts
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