P.1.5 Gene expression profiling identifies molecular pathways associated with collagen VI deficiency

Abstract

Ullrich Congenital Muscular Dystrophy (UCMD), caused by collagen VI deficiency, is a common cause of congenital muscular dystrophy. The clinical features include hypotonia, delayed motor milestones, proximal muscle weakness, distal joint hyperlaxity and proximal joint contractures within the first years of life. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied cDNA microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are significantly regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other forms of congenital muscular dystrophy. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significant regulated pathways were those involved in inflammatory response, regeneration and extracellular matrix remodelling. Moreover, we found that biglycan, an extracellular matrix proteoglycan that binds collagen VI, was markedly reduced from the basal lamina of UCMD patients. We propose that over-expression of biglycan may serve to improve UCMD pathophysiology by restoring the link between the muscle cell surface and the extracellular matrix. Taken together, our results provide new data about the physiopathology of collagen VI deficiency and point towards novel therapeutic approaches.