Gene expression profiling identifies molecular pathways associated with collagen VI deficiency and provides novel therapeutic targets.
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.
Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Materno-Infantil Sant Joan de Déu, Barcelona, Spain.
Sonia
S
Paco
Susana G
SG
Kalko
Cristina
C
Jou
María A
MA
Rodríguez
Joan
J
Corbera
Francesco
F
Muntoni
Lucy
L
Feng
Eloy
E
Rivas
Ferran
F
Torner
Francesca
F
Gualandi
Anna M
AM
Gomez-Foix
Anna
A
Ferrer
Carlos
C
Ortez
Andrés
A
Nascimento
Jaume
J
Colomer
Cecilia
C
Jimenez-Mallebrera
D016022:Case-Control Studies; D002648:Child; D024142:Collagen Type VI / Q000172:deficiency*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D058977:Molecular Sequence Annotation; D058990:Molecular Targeted Therapy; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D059748:Proteolysis; D012598:Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D059467:Transcriptome
D024142:Collagen Type VI