Mice with a deletion in the first intron of the Col1a1 gene develop age-dependent aortic dissection and rupture

Otto Rahkonen, Su Ming, Harri Hakovirta, Ilpo Koskivirta, Sheriar G. Hormuzdi, Eero Vuorio, Paul Bornstein, Risto Penttinen

    Research output: Contribution to journalArticlepeer-review

    47 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)83-90
    Number of pages8
    JournalCirculation Research
    Volume94
    Issue number1
    Early online date20 Nov 2003
    DOIs
    Publication statusPublished - 9 Jan 2004

    Fingerprint Dive into the research topics of 'Mice with a deletion in the first intron of the <em>Col1a1</em> gene develop age-dependent aortic dissection and rupture'. Together they form a unique fingerprint.

    Cite this