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


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.


CONCLUSIONS
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.
MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, UK. l.smith@hrsu.mrc.ac.uk
Lee B
LB
Smith
Patrick W F
PW
Hadoke
Emma
E
Dyer
Martin A
MA
Denvir
David
D
Brownstein
Eileen
E
Miller
Nancy
N
Nelson
Sara
S
Wells
Michael
M
Cheeseman
Andy
A
Greenfield
D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure; D024061:Collagen Type III / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion
D024061:Collagen Type III