Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type

PLoS One. 2016 Aug 12;11(8):e0161347. doi: 10.1371/journal.pone.0161347. eCollection 2016.


Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Biomarkers / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / pathology
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Profiling*
  • Humans
  • Joint Instability / genetics*
  • Joint Instability / pathology
  • Middle Aged
  • Phenotype
  • Skin Abnormalities / genetics*
  • Skin Abnormalities / pathology
  • Syndrome


  • Biomarkers

Supplementary concepts

  • Ehlers-Danlos syndrome type 3

Grant support

This work was supported by Fondazione Cariplo and Regione Lombardia supported the Open Access publication through the Grant “New Opportunities and Ways towards ERC” (NOW ERC, Project: 2014-2256) to NC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.