Rare Autosomal Recessive Cardiac Valvular Form of Ehlers-Danlos Syndrome Results from Mutations in the COL1A2 Gene That Activate the Nonsense-Mediated RNA Decay Pathway
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Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons. We identified three unrelated individuals with a rare recessively inherited form of EDS (characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon. The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and extremely unstable mRNA. In the wild-type allele, the two introns (IVS11 and IVS24) in which these mutations occurred were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. These findings suggest that the order of intron removal is an important variable in prediction of mutation outcome at splice sites and tha…
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In cardiac-valvular EDS, SDS PAGE demonstrates complete absence of (pro-)α2 chains of type I (pro)collagen extracted from dermis.
“SDS PAGE demonstrates complete absence of (pro-) a 2 chains of type I (pro) collagen extracted from dermis [Schwarze et al., 2004; Malfait et al., 2006].”
From The 2017 international classification of the Ehlers–Danlos syndromes (2017) · cites this paper as Schwarze et al., 2004
Seven different mutations have been reported in five independent cardiac-valvular EDS patients.
“Seven different mutations have been reported in five independent cardiacvalvular EDS patients.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
The hallmark of cardiac-valvular EDS is severe cardiac-valvular disease necessitating valve replacement surgery at adult age, in conjunction with variable skin hyperextensibility, atrophic scarring, joint hypermobility, and autosomal recessive inheritance.
“The hallmark of the condition is the severe cardiac-valvular disease, necessitating valve replacement surgery at adult age, in conjunction with variable skin hyperextensibility, atrophic scarring and joint hypermobility, and autosomal recessive inheritance.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
Because of the severe cardiac valve problems in most adult patients, this phenotype was called cardiac-valvular EDS.
“Because of the severe cardiac valve problems in most of the adult patients, this phenotype was called “cardiac-valvular EDS” [Schwarze et al., 2004].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
To date, six patients from five independent families have been reported with cardiac-valvular EDS, with age at diagnosis ranging from 6 to 65 years.
“To date, six patients from five independent families have been reported (Table S1).Their age at diagnosis ranged from 6 to 65 years [Hata et al., 1988;Kojima et al., 1988;Nicholls et al., 2001;Schwarze et al., 2004;Malfait et al., 2006].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
Cells from affected individuals produce type I collagen molecules that contain only proa1(I) chains.
“Cells from affected individuals produce type I collagen molecules that contain only proa1(I) chains.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
Schwarze et al. reported four patients from three independent families with a rare, recessively inherited form of EDS characterized by joint hypermobility, skin hyperextensibility, and severe cardiac-valvular defects, resulting from biallelic COL1A2 mutations leading to complete absence of proa2(I)-chains.
“Schwarze et al. [2004] reported four patients from three independent families (including the patient reported by Kojima et al. [1988]) with a rare, recessively inherited form of EDS, characterized by joint hypermobility, skin hyperextensibility, and severe cardiacvalvular defects, resulting from biallelic COL1A2 mutations, leading to complete absence of proa2(I)-chains.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al. [2004]
Biallelic COL1A2 mutations result in the complete absence of proa2(I) chains.
“The biallelic COL1A2 mutations result in the complete absence of proa2(I)chains.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
The mRNA from the mutant alleles is unstable and degraded so that no protein is produced.
“The mRNA from the mutant alleles is unstable and degraded so that no protein is produced.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Schwarze et al., 2004
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References 46 · Cited by 180
- Authors
- Schwarze, U., Hata, R.-I., McKusick, V. A., Shinkai, H., Hoyme, H. E., Pyeritz, R. E., & Byers, P. H.
- Affiliations
- University of Washington (US)
- Kanagawa Dental University (JP)
- Chiba University (JP)
- Stanford Medicine (US)
- University of Pennsylvania (US)
- Corresponding author
- Byers, Peter H.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 74
- Issue
- 5
- Pages
- 917-930
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1181985
- OpenAlex
- W2131252720
- Cited by
- 180
- References
- 46
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 4 · 2020: 9 · 2019: 16 · 2018: 4 · 2017: 14 · 2016: 6 · 2015: 9 · 2014: 6 · 2013: 17 · 2012: 12
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ar041223-11)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR41223, AR-21557, R01 AR041223, P01AR021557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Ehlers-Danlos syndrome, COL1A2, type I collagen, splice site mutation, nonsense-mediated mRNA decay, mRNA instability, cryptic splice donor site, exon skipping, mRNA folding, compound heterozygosity, homozygous nonsense mutation, valvular heart disease, autosomal recessive inheritance, osteogenesis imperfecta
- MeSH terms
- Adult, Aged, Base Sequence, Collagen, Ehlers-Danlos Syndrome, Exons, Female, Genes, Recessive, Heart Valve Diseases, Heterozygote, Humans, Introns, Male, Middle Aged, Molecular Sequence Data, Mutation, RNA Splicing, RNA, Messenger, Sequence Homology, Nucleic Acid, Skin, Protein Biosynthesis, Signal Transduction, Codon, Nonsense, RNA Stability, RNA Splice Sites, Collagen Type I
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