Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis
Open accessAbstract
Ehlers-Danlos syndrome type IV (EDS type IV) results from heterozygosity for mutations in the COL3A1 gene that encodes the chains of type III procollagen. By using light, transmission, and scanning electron microscopy, we examined skin biopsies from 22 individuals with EDS type IV in whom the COL3A1 mutations had been identified. The most striking changes in EDS type IV were correlated with point mutations that substituted a residue for a glycine near the carboxyl-terminal end of the triple-helical domain of pro alpha1(III). In three cases with the mutation G1012R, G1018V, or G1021E, cells in the dermis had extremely dilated rough endoplasmic reticulum (RER), the dermis was thin, and there was a reduced proportion of collagen although the proportion of elastic fibers appeared increased. In these tissues, collagen fibrils were small (65-80 nm) compared to normal (95-110 nm). Fibrils 80-90 nm in diameter and moderately dilated RER were found with mutations G769R, G373R, and G061E and with exon-skipping mutations of exons 34 and 45. With mutations G034R and G016C and exon-skipping mutations that deleted the sequences of exons 7, 8, 14, 18, 24, and 27, fibrils were more variable in size (85-120 nm). The composite collagen fibrils characteristic of EDS types I and II were not found in EDS type IV. These findings indicate that mutations in the COL3A1 gene have effects on secretion, fibrillogenesis, and skin architecture that reflect the position and nature of the mutation.
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Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and impairing the secretion and deposition into the ECM of functionally mature molecules.
“Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, thus altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and thereby impairing the secretion and deposition into the ECM of functionally mature molecules [95,96].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [95]
These mutations act through a dominant negative effect and are associated with the severe clinical spectrum of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures.
“through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures.”
The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain.
“The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain”
This type of mutations produces a dominant negative effect on the protein, thereby inhibiting extracellular accumulation of mature COLLIII.
“This type of mutations produces a dominant negative effect on the protein, thereby inhibiting extracellular accumulation of mature COLLIII.”
COL3A1 missense mutations altering glycine codons together with in-frame splice mutations in the triple helical domain lead to misfolding of COLLIII in the ER and retention of seven eighths of misfolded procollagen trimers in the cell with consequent enlargement of ER vesicles.
“COL3A1 missense mutations altering the glycine codons together with in-frame splice mutations in the triple helical domain account for the majority of disease-causing variants and lead to misfolding of COLLIII in the endoplasmic reticulum (ER) and retention of seven eighths of misfolded procollagen trimers in the cell with consequent enlargement of ER vesicles [8–10].”
The paper's molecular findings support that disturbance of ER-related homeostasis is associated with the disease mechanism as a result of abnormal protein folding with ensuing intracellular retention of mutant COLLIII chains and ER dilation.
“Overall our molecular findings may provide further support to early evidences suggesting that the disturbance of ER related homeostasis could be likely associated with the disease mechanism as a result of abnormal protein folding with ensuing intracellular retention of mutant COLLIII chains and ER dilation [8,53–55]”
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References 33 · Cited by 99
Research works printed but not linked: 2
- Deighton P: The Ehlcrs-D;:lI1los Sylldromes. In: I3cightoll. P (cd.). JVItKl/sirk's He,itaMc Disorders (l COIIl/crri,J(' TisSIIL'. 5th Ed. Mosby. Sr LOllis. MO. 1993. pp 189-252
- Byers PH: Disorders ofcollagclI structure alld synthesis. In: Scriver CR. Beaudet A. Sly W. Valle D (cds.). Tile ,\llt,tnu"lir 1/1/(/ J\/olcwlar HaSt'S (1' 1/l/f(:,.jfl~d Djsl!(J~'c. McGraw-HilI. New York.1995a, pp 4029-4078a Byers PH: Ehlers-Danlns syndrome type IV: :l generic disorder ill milny guises. Editorial COIllI11CI1[;lry.) .I1111t'S1 0/,,.,,/(/(01 105:31 '1-3'13. 19951->
- Authors
- Smith, L. T., Schwarze, U., Goldstein, J., & Byers, P. H.
- Affiliations
- University of Washington (US)
- ORCID
- Byers, Peter H.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 1997-03
- Volume
- 108
- Issue
- 3
- Pages
- 241-247
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2006919496
- Cited by
- 99
- References
- 33
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 7 · 2012: 4
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-21557, P01AR021557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- Ehlers-Danlos syndrome type IV, COL3A1 mutation, type III procollagen, dermis, rough endoplasmic reticulum dilation, elastic fibers, exon skipping, glycine substitution, triple-helical domain, fibril formation, skin anatomy
- MeSH terms
- Adult, Collagen, Ehlers-Danlos Syndrome, Fibroblasts, Humans, Microscopy, Electron, Middle Aged, Protein Conformation, Skin, Point Mutation, Endoplasmic Reticulum, Rough
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