Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome
Open accessAbstract
AIMS: The vascular type of Ehlers-Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45-50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-α(1) chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line. METHODS AND RESULTS: Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1-39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall. CONCLUSION: This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.
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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.
“Currently, there are two available mouse models for vEDS, both are homozygous or heterozygous nulls, which represent only about 5% or less of all known cases of vEDS patients [13–15].”
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Cites
Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type
Pepin, M., Schwarze, U., Superti-Furga, A., & Byers, P. H. (2000) · New England Journal of Medicine · doi:10.1056/nejm200003093421001 · Cited by 1,344 · see citing works
Tanaka, M., Yamamoto, Y., Misawa, E., Nabeshima, K., Saito, M., Yamauchi, K., Abe, F., & Furukawa, F. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000454718 · Cited by 1,092 · see citing works
Liu, X., Wu, H., Byrne, M., Krane, S., & Jaenisch, R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.5.1852 · Cited by 614 · see citing works
Heritable Diseases of Collagen
Prockop, D. J., & Kivirikko, K. I. (1984) · New England Journal of Medicine · doi:10.1056/nejm198408093110606 · Cited by 566 · see citing works
Martin, W., Furchgott, R. F., Villani, G. M., et al. (1986) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24986-2 · Cited by 373 · see citing works
Collagen characterisation and cell transformation in human atherosclerosis
MCCULLAGH, K. A., & Balian, G. (1975) · Nature · doi:10.1038/258073a0 · Cited by 224 · see citing works
Schwarze, U., Schievink, W. I., Petty, E., Jaff, M. R., Babovic-Vuksanovic, D., Cherry, K. J., Pepin, M., & Byers, P. H. (2001) · The American Journal of Human Genetics · doi:10.1086/324123 · Cited by 184 · see citing works
A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms.
Kontusaari, S., Tromp, G. C., Kuivaniemi, H., Romanic, A. M., & Prockop, D. J. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114863 · Cited by 182 · see citing works
Synthesis of types I and III procollagen and collagen by monkey aortic smooth muscle cells in vitro
Burke, J. M., Balian, G., Ross, R., et al. (1977) · Biochemistry · doi:10.1021/bi00633a031 · Cited by 152 · see citing works
Clinical and Genetic Features of Ehlers–Danlos Syndrome Type IV, the Vascular Type
(2001) · New England Journal of Medicine · doi:10.1056/nejm200102013440522 · Cited by 138 · see citing works
Influence of the vascular endothelium on agonist‐induced contractions and relaxations in rat aorta
Bullock, G., Taylor, S. G., & Weston, A. H. (1986) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1986.tb11187.x · Cited by 137 · see citing works
Mayer, S. A., Rubin, B. S., Starman, B. J., & Byers, P. H. (1996) · Neurology · doi:10.1212/wnl.47.2.552 · Cited by 86 · see citing works
Rahkonen, O. P., Su, M., Hakovirta, H. H., Koskivirta, I., Hormuzdi, S. G., VUORIO, E. I., BORNSTEIN, P. K., & Penttinen, R. P. K. (2003) · Circulation Research · doi:10.1161/01.res.0000108263.74520.15 · Cited by 83 · see citing works
Hadoke, P. W. F., Christy, C., Kotelevtsev, Y. V., Williams, B. C., Kenyon, C. J., Seckl, J. R., Mullins, J. J., & Walker, B. R. (2001) · Circulation · doi:10.1161/hc4801.100077 · Cited by 79 · see citing works
Self-citationKaneko, K., & Sunano, S. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90898-r · Cited by 75 · see citing works
Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome
Plancke, A., Holder‐Espinasse, M., Rigau, V., Manouvrier‐Hanu, S., Claustres, M., & Kien, P. K. V. (2009) · European Journal of Human Genetics · doi:10.1038/ejhg.2009.76 · Cited by 51 · see citing works
The Haploinsufficient <i>Col3a1</i> Mouse as a Model for Vascular Ehlers-Danlos Syndrome
Cooper, T. K., Zhong, Q., Krawczyk, M., Tae, H.-J., Müller, G. A., Schubert, R., Myers, L. A., Dietz, H. C., Talan, M. I., & Briest, W. (2010) · Veterinary Pathology · doi:10.1177/0300985810374842 · Cited by 51 · see citing works
Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm
Jones, J. A., Barbour, J. R., Stroud, R. E., Bouges, S., Stephens, S. L., Spinale, F. G., & Ikonomidis, J. S. (2008) · Journal of Vascular Research · doi:10.1159/000127437 · Cited by 43 · see citing works
Kuivaniemi, H., Tromp, G. C., Bergfeld, W. F., Kay, M., & Helm, T. N. (1995) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12320704 · Cited by 39 · see citing works
Meienberg, J., Rohrbach, M., Neuenschwander, S., Spanaus, K. S., Giunta, C., Alonso, S., Arnold, E., Henggeler, C., Regenass, S., Patrignani, A., et al. (2010) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.105 · Cited by 38 · see citing works
Improved system for measuring systolic blood pressure in the conscious rat
Evans, A., Brown, W. C., Kenyon, C. J., et al. (1994) · Medical & Biological Engineering & Computing · doi:10.1007/bf02512487 · Cited by 36 · see citing works
Aortic dissection: a rare complication of osteogenesis imperfecta.
Isotalo, P. A., Guindi, M. M., Bédard, P., et al. (1999) · PubMed · Cited by 33 · see citing works
Marjamaa, J., Tulamo, R. M., Abo‐Ramadan, U., Hakovirta, H. H., Frösén, J., Rahkonen, O., Niemela, M. R., BORNSTEIN, P. K., Penttinen, R. P. K., & Kangasniemi, M. (2006) · Magnetic Resonance in Medicine · doi:10.1002/mrm.20798 · Cited by 23 · see citing works
The Maestro (Mro) Gene Is Dispensable for Normal Sexual Development and Fertility in Mice
Smith, L. B., Willan, J., Warr, N., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0004091 · Cited by 9 · see citing works
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Sorted by citations
The good and the bad collagens of fibrosis – Their role in signaling and organ function
Karsdal, M. A., Nielsen, S. H., Leeming, D. J., Langholm, L. L., Nielsen, M. J., Manon-Jensen, T., Siebuhr, A., Gudmann, N. S., Rønnow, S., Sand, J. M., et al. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.07.014 · Cited by 509 · see citing works
Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome
Byers, P. H., Belmont, J., Black, J., De Backer, J., Frank, M., Jeunemaitre, X., Johnson, D., Pepin, M., Robert, L., Sanders, L., et al. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31553 · Cited by 381 · see citing works
The neurovascular link in health and disease: molecular mechanisms and therapeutic implications
Quaegebeur, A., Lange, C., & Carmeliet, P. (2011) · Neuron · doi:10.1016/j.neuron.2011.07.013 · Cited by 247 · see citing works
Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm
Jana, S., Hu, M., Shen, M., & Kassiri, Z. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0286-3 · Cited by 226 · see citing works
Vascular aspects of the Ehlers-Danlos Syndromes
Malfait, F. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.04.013 · Cited by 113 · see citing works
D'hondt, S., Guillemyn, B., Syx, D., Symoens, S., De Rycke, R., Vanhoutte, L., Toussaint, W., Lambrecht, B. N., De Paepe, A., Keene, D. R., et al. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.03.008 · Cited by 79 · see citing works
Chiarelli, N., Carini, G., Zoppi, N., Ritelli, M., & Colombi, M. (2018) · PLOS ONE · doi:10.1371/journal.pone.0191220 · Cited by 45 · see citing works
- Authors
- Smith, L. B., Hadoke, P. W. F., Dyer, E., Denvir, M. A., Brownstein, D., Miller, E., Nelson, N., Wells, S., Cheeseman, M., & Greenfield, A.
- Affiliations
- The Queen's Medical Research Institute (GB)
- Mary Lyon Centre at MRC Harwell (GB)
- Medical Research Council (GB)
- Corresponding author
- Smith, Lee B.
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-11-10
- Volume
- 90
- Issue
- 1
- Pages
- 182-190
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC3058731
- OpenAlex
- W1984138395
- Cited by
- 81
- References
- 24
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 9 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 2
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Cardiovascular Research (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- British Heart Foundation
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic aneurysm repair treatments
- Keywords
- vascular Ehlers-Danlos syndrome, COL3A1, type III collagen, haploinsufficiency, aortic dissection, collagen fibrillogenesis, arterial rupture, mouse lines
- MeSH terms
- Aortic Dissection, Animals, Blood Pressure, Disease Models, Animal, Ehlers-Danlos Syndrome, Exons, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Promoter Regions, Genetic, Sequence Deletion, Aortic Aneurysm, Thoracic, Genetic Predisposition to Disease, Collagen Type III, Mice, Mice, 129 Strain, Haploinsufficiency
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