title: Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators.
abstract: BACKGROUND
  Collagen 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.
  
  
  OBJECTIVE
  In 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.
  
  
  RESULTS
  We 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.
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Paco
authors.affiliation: Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Casserras
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Maria Angels
authors.initials: MA
authors.lastname: Rodríguez
authors.affiliation: Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Puigdelloses
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Carlos I
authors.initials: CI
authors.lastname: Ortez
authors.affiliation: Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Diaz-Manera
authors.affiliation: Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Nascimento
authors.affiliation: Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain.
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jimenez-Mallebrera
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D039422:Integrin alpha3 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D012598:Sclerosis / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
chemical_list: D039422:Integrin alpha3; D035683:MicroRNAs; D001205:Ascorbic Acid