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Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood
Open accessAbstract
Mutations in the COL1A1 and COL1A2 genes, encoding the proalpha1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the alpha1(I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show alpha1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.1053C>T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1839C>T; R396C (p.R574C); Y-position] and 3 [c.3396C>T; R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide-bonded alpha1(I)-dimers in approximately 20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant alpha1(I)-collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N-proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R-to-C substitutions in the alpha1(I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow-up of patients carrying this type of mutation.
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“Malfait et al. [2007] identified the same mutation in an adult who suffered from a rupture of medium-sized arteries, reminiscent of vascular EDS.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al. [2007]
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“In addition, two other arginine-to-cysteine (Arg-to-Cys) substitutions in the proa1(I) chain of type I collagen, c.1720C>T, p.(Arg574Cys) and c.3277C>T, p.(Arg1093Cys°), were identified in two other adults with vascular rupture, but without EDS-signs [Malfait et al., 2007].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2007
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“Ultrastructural studies of dermal collagen fibrils have shown fibrils with variable diameters, and slightly irregular contour, and, in case of the p.(Arg312Cys), flower-like abnormalities [Malfait et al., 2007].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2007
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“The hallmark of this condition is the “vascular fragility,” leading to spontaneous dissection or rupture of medium-sized arteries, in combination with other EDS signs.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2007
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“Patients with the p.(Arg312Cys) mutation are particularly at risk for vascular events, highlighting the benefit of molecular confirmation in classical EDS patients for management purposes.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al. [2007]
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Metadata
- Authors
- Malfait, F., Symoens, S., De Backer, J., Hermanns-Lê, T., Sakalihasan, N., Lapière, C. M., Coucke, P., & De Paepe, A.
- Affiliations
- Ghent University Hospital (BE)
- Centre Hospitalier Universitaire de Liège (BE)
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2007
- Volume
- 28
- Issue
- 4
- Pages
- 387-395
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- OpenAlex
- W1984751116
- Cited by
- 167
- References
- 33
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 12 · 2023: 3 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 5 · 2017: 13 · 2016: 8 · 2015: 11 · 2014: 10 · 2013: 14 · 2012: 9
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion)
- Funders
- Universiteit Gent
- Vlaamse regering
- 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
- Physical Sciences › Materials Science › Biomaterials › Collagen: Extraction and Characterization
- Keywords
- Ehlers-Danlos syndrome, type I collagen, alpha1(I) collagen, arterial dissection, arterial rupture, COL1A1, collagen triple helix, collagen fibrillogenesis, procollagen processing, collagen stability, osteopenia, genetic counseling
- MeSH terms
- Collagen Type I, alpha 1 Chain, Adolescent, Adult, Arginine, Base Sequence, Bone Diseases, Metabolic, Collagen, Cysteine, Ehlers-Danlos Syndrome, Female, Femoral Artery, Humans, Iliac Artery, Male, Molecular Sequence Data, RNA, Messenger, Rupture, Spontaneous, Protein Structure, Secondary, Amino Acid Substitution, Mutation, Missense, Collagen Type I, Collagen Type III
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