Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Apr 1;90(1):182-90.
doi: 10.1093/cvr/cvq356. Epub 2010 Nov 10.

Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome

Lee B Smith  1 , Patrick W F Hadoke, Emma Dyer, Martin A Denvir, David Brownstein, Eileen Miller, Nancy Nelson, Sara Wells, Michael Cheeseman, Andy Greenfield
Affiliations

Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome

Lee B Smith et al. Cardiovasc Res. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Phenotypic presentation is characterized by haemothorax resulting from acute aortic dissection. (A) Partially dissected tissues showing the tongue, cranial mediastinum, and lungs showing clear evidence of haemothorax (the primary phenotypic presentation following sudden death in this mouse colony) coating the lungs (arrow). Bar = 1 cm. (B) Longitudinal section through the aortic root from an affected mouse showing aortic dissection (boxed); for orientation, the heart (H) is included in the image (L = aortic lumen). Bar = 1 mm. (C) Magnification of the site of dissection [boxed area in (B)] clearly shows haemorrhage into the aortic wall and mediastinum, with the external wall of the aorta dissected away from the main structure (arrowed) (L = aortic lumen). Bar = 1 mm. (D) Magnification [boxed area in (C)] shows the disruption of the elastic lamellae with erythrocytes visible within the aortic wall (arrow). Bar = 100 µm. (E) Longitudinal section through the descending thoracic aorta taken from a second affected animal. The site of dissection is clearly visible, characterized by complete disruption of the elastic lamellae. The opposing wall of the vessel is unaffected (arrow). Bar = 100 µm. (All samples: Elastic van Gieson stain.)
Figure 2
Figure 2
Affected animals die prematurely, with evidence of a sex ratio bias. A comparison of age at death in confirmed cases of aortic dissection reveals 77% of deaths occur between 4 and 10 weeks of age. Peak incidence of death is similar in both sexes; however, beyond 13 weeks, while the frequency of deaths is reduced, the majority of deaths that do occur are male animals (10 males:1 female).
Figure 3
Figure 3
The aortic dissection phenotype results from a 185 kb deletion of chromosome 1 spanning the putative regulatory region and exons 1–39 of the procollagen gene Col3α1. (A) Schematic representation of the proximal end of mouse chromosome 1 highlighting the location of the three informative SNP markers initially used to haplotype the region. (B) Magnified view of a section of chromosome 1; the absence of the allele from the 129Ola genome at SNP rs3656719 in all affected animals was suggestive of a deletion in this region. (C) PCR amplification using primers ostensibly 185 kb apart (marked on schematic as red arrows) produces an amplicon of 172 bp in affected animals. (D) DNA sequencing of this amplicon identifies the deletion breakpoints in chromosome 1 and confirms the deletion to be 185 kb in size, including 145 kb of the putative regulatory region and exons 1–39 of the Col3a1gene. The allele is named Col3a1▵.
Figure 4
Figure 4
Aortas of 4-week-old +/Col3a1▵ mice display evidence of ultrastructural abnormalities. The ultrastructure of aortas of 4-week-old +/+ and +/Col3a1▵ animals (n= 3 per group) were examined using transmission electron microscopy. Aortas taken from +/+ animals display continuous elastic laminae (*) with a consistent width (A). Conversely, elastic lamellae in +/Col3a1▵ animals (*) display reduced electron density when compared with +/+ animals (all sections were 60 nm thick) along with variable width and a disrupted architecture (B). Evidence of disruption to the elastic lamellae (black arrow) and tearing of the smooth muscle layer (white arrows) is evident in all +/Col3a1▵ animals examined (C), which in one animal had resulted in shearing of the smooth muscle layer and entry of erythrocytes into the aortic media (D and E) (arrow in E = elastic lamellae). Shearing of the smooth muscle layer is associated with structural abnormalities in collagen fibres (arrow), which unlike in +/+ mice (F), fail to form correctly (arrows) (G). L, aortic lumen; m, aortic media; r, erythrocytes; sm, smooth muscle; Le, leucocyte (A–E bar = 5 μm; F and G, bar = 2 μm).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Prockop DJ, Kivirikko KI. Heritable diseases of collagen. N Engl J Med. 1984;311:376–386. doi:10.1056/NEJM198408093110606. - DOI - PubMed
    1. Kontusaari S, Tromp G, Kuivaniemi H, Romanic AM, Prockop DJ. A mutation in the gene for type-III procollagen (Col3A1) in a family with aortic-aneurysms. J Clin Invest. 1990;86:1465–1473. doi:10.1172/JCI114863. - DOI - PMC - PubMed
    1. Kuivaniemi H, Tromp G, Bergfeld WF, Kay M, Helm TN. Ehlers–Danlos-syndrome type-IV—a single-base substitution of the last nucleotide of exon-34 in Col3A1 leads to exon skipping. J Invest Dermatol. 1995;105:352–356. doi:10.1111/1523-1747.ep12320704. - DOI - PubMed
    1. Burke JM, Balian G, Ross R, Bornstein P. Synthesis of Type-1 and Type-3 procollagen and collagen by monkey aortic smooth-muscle cells in vitro. Biochemistry. 1977;16:3243–3249. doi:10.1021/bi00633a031. - DOI - PubMed
    1. Mccullagh KA, Balian G. Collagen characterization and cell transformation in human atherosclerosis. Nature. 1975;258:73–75. doi:10.1038/258073a0. - DOI - PubMed

Publication types

MeSH terms

Substances