Classical Ehlers-Danlos Syndrome Caused by a Mutation in Type I Collagen

Nuytinck, Lieve; Freund, Margarida; Lagae, Lieven; Pierard, Gerald E.; Hermanns-Le, Trinh; De Paepe, Anne

doi:10.1086/302859

Cited by 169Connective tissue disorders researchDermatological and Skeletal DisordersCollagen: Extraction and Characterization

Classical Ehlers-Danlos Syndrome Caused by a Mutation in Type I Collagen

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Nuytinck, Lieve, Freund, Margarida, Lagae, Lieven, Pierard, Gerald E., Hermanns-Le, Trinh, De Paepe, Anne·2000·The American Journal of Human Genetics

DOI 10.1086/302859PMC PMC1288203

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Abstract

Classical Ehlers-Danlos syndrome (EDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, have been shown to underlie this type of EDS. However, to date, mutations have been found in only a limited number of patients, which suggests genetic heterogeneity. In this article, we report two unrelated patients with typical features of classical EDS, including excessive skin fragility, in whom we found an identical arginine-->cysteine substitution in type I collagen, localized at position 134 of the alpha1(I) collagen chain. The arginine residue is highly conserved and localized in the X position of the Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges are formed, resulting in type I collagen aggregates, which are retained in the cells. Whereas substitutions of glycine residues in type I collagen invariably result in osteogenesis imperfecta, substitutions of nonglycine residues in type I collagen have not yet been associated with a human disease. In contrast, arginine-->cysteine substitutions in type II collagen have been identified in a variety of chondrodysplasias. Our findings show that mutations in other fibrillar collagens can be causally involved in classical EDS and point to genetic heterogeneity of this disorder.

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Two children with a classical EDS phenotype including skin hyperextensibility, easy bruising, atrophic scarring, and joint hypermobility had the COL1A1 c.934C>T, p.(Arg312Cys) mutation.
“Nuytinck et al. [2000] reported two children with a classical EDS phenotype, including skin hyperextensibility, easy bruising, atrophic scarring, and joint hypermobility, with a c.934C>T, p.(Arg312Cys) mutation.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Nuytinck et al. [2000]
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 Nuytinck et al., 2000

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Authors: Nuytinck, L., Freund, M., Lagae, L., Pierard, G. E., Hermanns-Le, T., & De Paepe, A.
Affiliations: Ghent University Hospital (BE)
UCLouvain (BE)
Universitair Ziekenhuis Leuven (BE)
ORCID: Nuytinck, Lieve
Lagae, Lieven
Venue: The American Journal of Human Genetics
Publisher: Elsevier BV
Published: 2000-04
Volume: 66
Issue: 4
Pages: 1398-1402
ISSN: 0002-9297 (ISSN-L)
DOI: 10.1086/302859
PMC: PMC1288203
OpenAlex: W1966946871
Cited by: 169
References: 22
Citations by year: 2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 6 · 2016: 11 · 2015: 5 · 2014: 4 · 2013: 13 · 2012: 10
FWCI: 2.91
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4857 d)
Locations: The American Journal of Human Genetics (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Digital Access to Libraries (submittedVersion)
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: classical Ehlers-Danlos syndrome, type I collagen, disulfide bonds, skin fragility, joint hypermobility, genetic heterogeneity, type V collagen, fibrillar collagen, collagen fibrillogenesis
MeSH terms: Amino Acid Sequence, Arginine, Base Sequence, Child, Child, Preschool, Collagen, Cysteine, Disulfides, DNA Mutational Analysis, Ehlers-Danlos Syndrome, Exons, Female, Fibroblasts, Humans, Male, Mutation, Genetic Heterogeneity, Polymorphism, Single-Stranded Conformational, Dimerization, Amino Acid Substitution, Amino Acid Motifs

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Classical Ehlers-Danlos Syndrome Caused by a Mutation in Type I Collagen

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