Journal Article

Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets

Nascimento, Andrés, Paco, Sonia, Jou, Cristina, Kalko, Susana G., Ortez, Carlos, Muntoni, Francesco, Jimenez-Mallebrera, Cecilia, Gualandi, Francesca, Rodríguez, María A., Ferrer, Anna, Gomez-Foix, Anna M., Rivas, Eloy, Torner, Ferran, Colomer, Jaume, Corbera, Joan, Feng, Lucy

2013

Overview

Ullrich congenital muscular dystrophy (UCMD), caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially 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 congenital muscular dystrophies. 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 significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Apoptosis / Autophagy / Basal lamina / Biomedical research / Case-Control Studies / Cell surface / Child / Childrens health / Collagen / Collagen Type VI - deficiency / Congenital diseases / Distròfia muscular / DNA microarrays / Dystrophin / Dystrophy / Endoplasmic Reticulum - genetics / Endoplasmic Reticulum - metabolism / Expressió gènica / Extracellular matrix / Extracellular Matrix - metabolism / Gene expression / Gene Expression Profiling / Genes / Genes, MHC Class II / Genetic aspects / Genetic disorders / Genètica molecular humana / Health aspects / Hospitals / Human molecular genetics / Humans / Immune response / Immune system / Inflammation / Macrophages / Mitochondria - genetics / Mitochondria - metabolism / Molecular chains / Molecular Sequence Annotation / Molecular Targeted Therapy / Muscle, Skeletal - metabolism / Muscles / Muscular Dystrophies - genetics / Muscular Dystrophies - metabolism / Muscular Dystrophies - therapy / Muscular dystrophy / Musculoskeletal system / Mutation / Neurology / Neuromuscular diseases / Oligonucleotide Array Sequence Analysis / Pathogenesis / Pathology / Proteolysis / Regeneration / Rodents / Sclerosis - genetics / Sclerosis - metabolism / Sclerosis - therapy / Therapeutic applications / Transcriptome / Utrophin