Published online before print November 20, 2003, doi: 10.1161/01.RES.0000108263.74520.15
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Submitted on February 20, 2003
Revised on November 5, 2003
Accepted on November 11, 2003
Mice With a Deletion in the First Intron of the Col1a1 Gene Develop Age-Dependent Aortic Dissection and Rupture
Otto Rahkonen ;
From the Department of Medical Biochemistry and Molecular Biology (O.R., I.K., E.V., R.P.), Research Centre of Applied and Preventive Cardiovascular Medicine (O.R), and Department of Surgery (H.H.), University of Turku, Finland, the CIHR Group in Matrix Dynamics (M.S), University of Toronto, Canada, and the Departments of Biochemistry and Medicine (S.H., P.B.), University of Washington, Seattle, Wash. Present address for S.G.H. is University Hospital of Neurology, Heidelberg, Germany.
* To whom correspondence should be addressed. E-mail: bornsten{at}u.washington.edu.
The functional significance of the first intron of the Col1a1 gene in regulation of type I collagen synthesis remains uncertain. A previous study in mice established that a mutated Col1a1 allele that lacked a large fraction of the first intron, but retained the sequences required for normal splicing, was subject to an age- and tissue-dependent decrease in expression. In this study, we report that mice homozygous for this deletion are predisposed to dissection and rupture of the aorta during their adult life. Aortic dissection was not detected in autopsies of heterozygous animals or their littermate controls. Electron micrographs revealed fewer collagen fibrils and less compacted, irregular elastic lamellae in the aortic walls of homozygous mutant animals. Northern analysis of aortic RNA from 2.5- and 12-month-old homozygous mutant mice revealed that Col1a1 mRNA levels were decreased by 29% and 42%, respectively, relative to those of control littermates. In 12-month-old heterozygotes, the decrease was 32%. Allele-specific amplification of heterozygous cDNAs demonstrated that this reduction was limited to transcripts from the mutant allele. The collagen content of the aortas of homozygous mutant mice was also significantly lower in comparison to that of age-matched, control animals. These data establish that the integrity of the aortic wall depends on an adequate content of type I collagen, and that continued synthesis of collagen in the aorta as a function of age is critically dependent on sequences in the first intron of the Col1a1 gene.
Key words: collagen • gene regulation • targeted mutation • RT-PCR • homologous recombination
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