Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development

Liu, Xin; Wu, Hong; Byrne, Michael; Krane, Stephen; Jaenisch, Rudolf

doi:10.1073/pnas.94.5.1852

Cited by 614Connective tissue disorders researchCollagen: Extraction and CharacterizationCellular Mechanics and Interactions

Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development

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Liu, Xin, Wu, Hong, Byrne, Michael, Krane, Stephen, Jaenisch, Rudolf·1997·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.94.5.1852PMC PMC20006

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Abstract

Type III collagen is a fibrillar forming collagen comprising three α1(III) chains and is expressed in early embryos and throughout embryogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin. Mutations in the COL3A1 gene have been implicated as a cause of type IV Ehlers–Danlos syndrome, a disease leading to aortic rupture in early adult life. To directly study the role of Col3a1 in development and disease, we have inactivated the Col3a1 gene in embryonic stem cells by homologous recombination. The mutated allele was transmitted through the mouse germ line and homozygous mutant animals were derived from heterozygous intercrosses. About 10% of the homozygous mutant animals survived to adulthood but have a much shorter life span compared with wild-type mice. The major cause of death of mutant mice was rupture of the major blood vessels, similar to patients with type IV Ehlers–Danlos syndrome. Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs.

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Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and impairing the secretion and deposition into the ECM of functionally mature molecules.
“Most disease-causing variants in COL3A1 are glycine substitutions that destroy the triple helical winding, thus altering the structural integrity of collagen III due to misfolded procollagen III in the ER, and thereby impairing the secretion and deposition into the ECM of functionally mature molecules [95,96].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [96]
Col3a1+/− mice present a very mild phenotype, as suggested by a low incidence of vascular events.
“While Col3a1+/− mice present a very mild phenotype, as suggested by a low incidence of vascular events”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [13]
Homozygotes exhibit a severe perinatal mortality owing to arterial ruptures.
“homozygotes exhibit a severe perinatal mortality owing to arterial ruptures [13].”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [13]
Two available mouse models for vEDS are homozygous or heterozygous nulls, which represent only about 5% or less of all known cases of vEDS patients.
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From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [13]

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Authors: Liu, X., Wu, H., Byrne, M., Krane, S., & Jaenisch, R.
Affiliations: Harvard University (US)
ORCID: Liu, Xin
Wu, Hong
Jaenisch, Rudolf
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1997-03-04
Volume: 94
Issue: 5
Pages: 1852-1856
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.94.5.1852
PMC: PMC20006
OpenAlex: W2079738970
Cited by: 614
References: 28
Citations by year: 2026: 25 · 2025: 26 · 2024: 38 · 2023: 25 · 2022: 31 · 2021: 35 · 2020: 41 · 2019: 25 · 2018: 32 · 2017: 34 · 2016: 22 · 2015: 27 · 2014: 26 · 2013: 27 · 2012: 18
FWCI: 5.07
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r35ca044339-13, 5p01ar003564-38)
National Cancer Institute (R-35-CA44339)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-3564)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Physical Sciences › Materials Science › Biomaterials › Collagen: Extraction and Characterization
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords: type III collagen, COL3A1, cardiovascular development, Ehlers-Danlos syndrome type IV, aortic rupture, mouse mutants, extracellular matrix, lifespan, vascular rupture
MeSH terms: Animals, Aorta, Cardiovascular System, Cells, Cultured, Collagen, Disease Models, Animal, Ehlers-Danlos Syndrome, Histocytochemistry, Mice, Transgenic, Microscopy, Electron, Myocardium, Skin, Stem Cells, Blotting, Southern, Restriction Mapping, Sequence Deletion, Gene Targeting, Mice

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Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development

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