Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts
Open accessAbstract
Classical Ehlers-Danlos syndrome (cEDS) is a dominant inherited connective tissue disorder mainly caused by mutations in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV), which is a fibrillar COLL widely distributed in a variety of connective tissues. cEDS patients suffer from skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. Most of the causative variants result in a non-functional COL5A1 allele and COLLV haploinsufficiency, whilst COL5A2 mutations affect its structural integrity. To shed light into disease mechanisms involved in cEDS, we performed gene expression profiling in skin fibroblasts from four patients harboring haploinsufficient and structural mutations in both disease genes. Transcriptome profiling revealed significant changes in the expression levels of different extracellular matrix (ECM)-related genes, such as SPP1, POSTN, EDIL3, IGFBP2, and C3, which encode both matricellular and soluble proteins that are mainly involved in cell proliferation and migration, and cutaneous wound healing. These gene expression changes are consistent with our previous protein findings on in vitro fibroblasts from other cEDS patients, which exhibited reduced migration and poor wound repair owing to COLLV disorganization, altered deposition of fibronectin into ECM, and an abnormal integrin pattern. Microarray analysis also indicated the decreased expression of DNAJB7, VIPAS39, CCPG1, ATG10, SVIP, which encode molecular chaperones facilitating protein folding, enzymes regulating post-Golgi COLLs processing, and proteins acting as cargo receptors required for endoplasmic reticulum (ER) proteostasis and implicated in the autophagy process. Patients' cells also showed altered mRNA levels of many cell cycle regulating genes including CCNE2, KIF4A, MKI67, DTL, and DDIAS. Protein studies showed that aberrant COLLV expression causes the disassembly of itself and many structural ECM constituents including COLLI, COLLIII, fibronectin, and fibrillins. Our findings provide the first molecular evidence of significant gene expression changes in cEDS skin fibroblasts highlighting that defective ECM remodeling, ER homeostasis and autophagy might play a role in the pathogenesis of this connective tissue disorder.
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cEDS cells exhibit reduced in vitro migration capability.
“cEDS cells also exhibit a reduced in vitro migration capability, an abnormal wound healing response, and a crosstalk involving the αvβ3 integrin and epidermal growth factor (EGF) receptor that rescues them from anoikis [44,45,46,47,48,49,50].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
cEDS cells exhibit an abnormal wound healing response.
“cEDS cells also exhibit a reduced in vitro migration capability, an abnormal wound healing response, and a crosstalk involving the αvβ3 integrin and epidermal growth factor (EGF) receptor that rescues them from anoikis [44,45,46,47,48,49,50].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
Transcriptome profiling of cEDS fibroblasts showed dysregulated expression of many genes encoding matricellular and soluble proteins with prominent functions in cell proliferation and migration, collagen assembly and ECM remodeling during wound healing, i.e., SPP1, POSTN, EDIL3, IGFBP2, and C3.
“Transcriptome profiling of cEDS fibroblasts added new insights into the complex molecular mechanisms involved in the maintenance of ECM homeostasis and proper wound healing, since patients’ cells showed the dysregulated expression of many genes encoding matricellular and soluble proteins with prominent functions in cell proliferation and migration, collagen assembly and ECM remodeling during wound”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
cEDS cells exhibit a crosstalk involving the αvβ3 integrin and EGF receptor that rescues them from anoikis.
“cEDS cells also exhibit a reduced in vitro migration capability, an abnormal wound healing response, and a crosstalk involving the αvβ3 integrin and epidermal growth factor (EGF) receptor that rescues them from anoikis [44,45,46,47,48,49,50].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
cEDS patients' fibroblasts show disorganization of collagen- and fibronectin-specific α2β1 and α5β1 integrin receptors.
“Our in vitro findings demonstrated that cEDS patients’ fibroblasts show disassembly of many ECM components, including collagen V and III, fibronectin, and fibrillins, and disorganization of collagen- and fibronectin-specific α2β1 and α5β1 integrin receptors [44,45,46,47].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
cEDS patients' fibroblasts show disassembly of many ECM components, including collagen V and III, fibronectin, and fibrillins.
“Our in vitro findings demonstrated that cEDS patients’ fibroblasts show disassembly of many ECM components, including collagen V and III, fibronectin, and fibrillins, and disorganization of collagen- and fibronectin-specific α2β1 and α5β1 integrin receptors [44,45,46,47].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
In cEDS fibroblasts, a possible unbalance of ER homeostasis and autophagy was assumed given the decreased expression of many associated genes such as DNAJB7, ATG10, CCPG1, and SVIP.
“In cEDS fibroblasts, a possible unbalance of ER homeostasis and autophagy was assumed given the decreased expression of many associated genes such as DNAJB7, ATG10, CCPG1, and SVIP [47].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [47]
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Complement C3 Exacerbates Imiquimod-Induced Skin Inflammation and Psoriasiform Dermatitis
Giacomassi, C., Buang, N. B., Ling, G. S., Crawford, G., Cook, H. T., Scott, D. M., Dazzi, F., Strid, J., & Botto, M. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.11.011 · Cited by 22 · see citing works
Zoppi, N., Ritelli, M., & Colombi, M. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.06.004 · Cited by 21 · see citing works
Self-citationWang, Z., Tran, M. C., Bhatia, N., Hsing, A. W., Chen, C. C. L., Russa, M. F. L., Fattakhov, E., Rashidi, V., Jang, K. Y., Choo, K. J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0160684 · Cited by 14 · see citing works
Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997
Beighton, P., Paepe, A. D., Steinmann, B., Tsipouras, P., & Wenstrup, R. J. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980428)77:1
Flagged first, then by citations
Cited by
Sorted by citations
Chiarelli, N., Ritelli, M., Zoppi, N., & Colombi, M. (2019) · Genes · doi:10.3390/genes10080609 · Cited by 82 · see citing works
Self-citationScicluna, K., Formosa, M. M., Farrugia, R., & Borg, I. (2022) · Clinical Genetics · doi:10.1111/cge.14026 · Cited by 20 · see citing works
- Authors
- Chiarelli, N., Carini, G., Zoppi, N., Ritelli, M., & Colombi, M.
- Affiliations
- University of Brescia (IT)
- Corresponding author
- Colombi, Marina
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-02-04
- Volume
- 14
- Issue
- 2
- Pages
- e0211647
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6361458
- OpenAlex
- W2911609224
- Cited by
- 35
- References
- 86
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 6 · 2020: 3 · 2019: 1
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- classical Ehlers-Danlos syndrome, type V collagen, COL5A1, COL5A2, haploinsufficiency, dermal fibroblasts, gene expression profiling, extracellular matrix remodeling, wound healing, matricellular proteins, autophagy, endoplasmic reticulum proteostasis, cell cycle genes, connective tissue diseases, gene expression changes
- MeSH terms
- Adult, Alleles, Cell Cycle, Cells, Cultured, Collagen, Connective Tissue, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Extracellular Matrix, Female, Fibroblasts, Fibronectins, Humans, Male, Middle Aged, Mutation, RNA, Messenger, Skin, Skin Abnormalities, Case-Control Studies, Gene Expression Profiling, Haploinsufficiency, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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