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Cited by 167Connective tissue disorders researchDermatological and Skeletal DisordersCollagen: Extraction and Characterization

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

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Malfait, Fransiska, Symoens, Sofie, De Backer, Julie, Hermanns-Lê, Trinh, Sakalihasan, Natzi, Lapière, Charles M., Coucke, Paul, De Paepe, Anne·2007·Human Mutation
DOI 10.1002/humu.20455
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Abstract

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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  • The COL1A1 p.(Arg312Cys) mutation was identified in an adult who suffered a rupture of medium-sized arteries reminiscent of vascular EDS.

    “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]

    The Mutation Detection section identifies COL1A1 p.R312C in Patient 1, and Table 2 records a right iliac artery event at age 37. But Table 2 and the Results describe that event as a dissection, not a rupture. The Discussion compares the arterial phenotype with vascular EDS, so the resemblance is supported. (LLM, conf=0.87)

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  • Two other 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 adults with vascular rupture but without EDS signs.

    “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

    The Abstract identifies the two substitutions in Patients 2 and 3, and Results: Clinical Description says the two had osteopenia rather than classic EDS signs. However, Results and Table 2 describe their vascular events as arterial dissections and aneurysms, not documented vascular ruptures; the paper describes rupture as a propensity or future risk. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Ultrastructural studies of dermal collagen fibrils have shown fibrils with variable diameters, slightly irregular contour, and, in p.(Arg312Cys), flower-like abnormalities.

    “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

  • The hallmark of the COL1A1 p.(Arg312Cys) condition is vascular fragility, leading to spontaneous dissection or rupture of medium-sized arteries, in combination with other EDS signs.

    “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

  • Patients with the COL1A1 p.(Arg312Cys) mutation are particularly at risk for vascular events.

    “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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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)
ORCID
Venue
Human Mutation
Publisher
Hindawi Limited
Published
2007
Volume
28
Issue
4
Pages
387-395
ISSN
  • 1059-7794 (ISSN-L)
  • 1098-1004
DOI
10.1002/humu.20455
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
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 3165 d)
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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