P.1.4 Gene expression profile of collagen VI deficient human fibroblasts

Abstract

Ullrich Congenital Muscular Dystrophy (UCMD), caused by collagen VI deficiency, is one of the most common inherited myopathies. It is characterized by hypotonia, delayed motor milestones, proximal muscle weakness, distal joint hyperlaxity and proximal joint contractures within the first year of life. Furthermore, a characteristic skin phenotype has been described. UCMD is caused by recessive or dominant mutations in any of the three collagen 6 genes (COL6A1, COL6A2 and COL6A3) which result in an absence or partial deficiency of collagen VI around the muscle fibre. Collagen VI is produced by resident endomysial fibroblasts. Once secreted into the extracellular matrix (ECM), collagen VI fibrils interact with the muscle cell via yet unknown receptors. In order to gain insight into the molecular pathogenesis of collagen VI defects we have performed gene expression microarray analysis of dermal fibroblasts. We have compared the transcriptome of fibroblasts, treated with ascorbic acid to allow for correct post-translational processing and secretion of collagen molecules or untreated, from UCMD patients (<i>n</i>=6) and from aged-matched healthy children (<i>n</i>=6). Herein we summarise the results of the analysis of the expression data. We have identified significant changes in over 600 transcripts in UCMD fibroblasts relative to normal fibroblasts, both before and after ascorbic acid treatment. Bioinformatics analysis using Gene Ontology, KEGG and Ingenuity Pathways tools showed that the most significantly altered pathways were related to ECM organisation, TGF-β signalling, cell proliferation, protein secretion and lipid and steroid metabolism. We found changes in numerous ECM, basal lamina and cell surface components. For example, we found up-regulation of CD44 and integrins alpha 3, 6 and 7 in UCMD fibroblasts compared to control fibroblasts (independently of ascorbic acid treatment). Collagen, laminins and tenascin genes were also affected.