Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV)
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Purpose We sought to characterize the natural history of vascular Ehlers-Danlos syndrome in individuals with heterozygous COL3A1 mutations.Methods We reviewed clinical records for details of vascular, bowel, and organ complications in 1,231 individuals (630 index cases and 601 relatives).Results Missense and splice-site mutations accounted for more than 90% of the 572 alterations that we had identified in COL3A1. Median survival was 51 years but was influenced by gender (lower in men) and by the type of mutation.Conclusion Although vascular Ehlers-Danlos syndrome appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1. These findings indicate that when counseling families, confirmation of the presence of a COL3A1 mutation and its nature can help evaluate the risks of complications. These data are also important ingredients in both the selection and allocation of individuals to appropriate arms in clinical trials to assess the effects of interventions.
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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”
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.”
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.”
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).
“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).”
The nature of the specific COL3A1 mutation influences life expectancy.
“the nature of the specific COL3A1 mutation influences life expectancy.”
Splice site mutations that lead to exon skipping have the lowest median survival.
“Splice site mutations that lead to exon skipping have the lowest median survival.”
Heterozygosity for COL3A1 null alleles typically produces a milder clinical phenotype with a significant delayed onset of complications.
“Heterozygosity for COL3A1 null alleles typically produces a milder clinical phenotype with a significant delayed onset of complications [4, 9–12].”
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 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.
“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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- Authors
- Pepin, M. G., Schwarze, U., Rice, K. M., Liu, M., Leistritz, & Byers, P. H.
- Affiliations
- University of Washington (US)
- Corresponding author
- Pepin, Melanie G.
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 16
- Issue
- 12
- Pages
- 881-888
- ISSN
- 1098-3600 (ISSN-L)
- OpenAlex
- W2030732677
- Cited by
- 313
- References
- 16
- Citations by year
- 2026: 29 · 2025: 30 · 2024: 35 · 2023: 29 · 2022: 37 · 2021: 27 · 2020: 24 · 2019: 30 · 2018: 26 · 2017: 18 · 2016: 16 · 2015: 10 · 2014: 2
- FWCI
- 10.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- 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 mutation, missense mutations, splice site mutation, natural history (disease), survival, allelic heterogeneity, gender differences, bowel complications, vascular complications, family counseling, clinical trial selection
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Child, DNA Mutational Analysis, Ehlers-Danlos Syndrome, Female, Humans, Male, Middle Aged, Mutation, RNA Splicing, Genetic Variation, Treatment Outcome, Mutation, Missense, Collagen Type III, Young Adult
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