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.