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The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome
Open accessAbstract
Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions-deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions-deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22-39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3-5, with extreme median ages at first major complication of 23-47 years. Patients of groups 3-5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.
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In the citing paper
“The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain”
In the citing paper
“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.”
In the citing paper
“the nature of the specific COL3A1 mutation influences life expectancy.”
In the citing paper
“Splice site mutations that lead to exon skipping have the lowest median survival.”
In the citing paper
“Heterozygosity for COL3A1 null alleles typically produces a milder clinical phenotype with a significant delayed onset of complications [4, 9–12].”
In the citing paper
“Substitutions of bulky residues (Arg, Asp, Glu, Val) for glycine residues in the triple helical domain are usually less severe than splice site mutations, but more consequential than substitutions by smaller residues (Ala, Ser, Cys).”
In the citing paper
“This type of mutations produces a dominant negative effect on the protein, thereby inhibiting extracellular accumulation of mature COLLIII.”
In the citing paper
“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].”
In the citing paper
“Besides, the present patients exhibited a full-blown expression of the disease with several major arterial events, in line with the limited genotype-phenotype correlation that associates this type of structural mutations with a more severe clinical phenotype [4,9–12].”
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Citations
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Cited by
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Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases
Kuivaniemi, H., & Tromp, G. (2019) · Gene · doi:10.1016/j.gene.2019.05.003 · Cited by 444
Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome
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Self-citationMalfait, F., Castori, M., Francomano, C. A., Giunta, C., Kosho, T., & Byers, P. H. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-0194-9 · Cited by 346
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Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications
Brownstein, A. J., Kostiuk, V., Ziganshin, B. A., Zafar, M. A., Kuivaniemi, H., Body, S. C., Bale, A. E., & Elefteriades, J. A. (2018) · Aorta · doi:10.1055/s-0038-1639612 · Cited by 179
Metadata
- Authors
- Frank, M., Albuisson, J., Ranque, B., Golmard, L., Mazzella, J.-M., Bal-Theoleyre, L., Fauret, A.-L., Mirault, T., Denarié, N., Mousseaux, E., Boutouyrie, P., Fiessinger, J.-N., Emmerich, J., Messas, E., & Jeunemaitre, X.
- Affiliations
- Inserm (FR)
- Sorbonne Paris Cité (FR)
- Hôpital de la Timone (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2015-03-11
- Volume
- 23
- Issue
- 12
- Pages
- 1657-1664
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC4795191
- OpenAlex
- W2030840013
- Cited by
- 248
- References
- 20
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 27 · 2023: 31 · 2022: 32 · 2021: 23 · 2020: 17 · 2019: 22 · 2018: 19 · 2017: 16 · 2016: 8 · 2015: 4
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-BLAN-1129)
- Institut National de la Santé et de la Recherche Médicale
- 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 › Genetics › Genomics and Rare Diseases
- Keywords
- vascular Ehlers-Danlos syndrome, COL3A1, type III collagen, disease severity, glycine substitution, splice site mutation, haploinsufficiency, missense mutations, triple helix, arterial rupture, genotype-phenotype correlation, genetic counseling
- MeSH terms
- Adult, Ehlers-Danlos Syndrome, Female, Humans, Male, Middle Aged, Phenotype, Gene Deletion, Mutation, Missense, Collagen Type III
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