Mice with a deletion in the first intron of the Col1a1 gene develop age-dependent aortic dissection and rupture.
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.
Rahkonen
Otto
O
Department of Medical Biochemistry and Molecular Biology, University of Turku, Finland. bornsten@u.washington.edu
Su
Ming
M
Hakovirta
Harri
H
Koskivirta
Ilpo
I
Hormuzdi
Sheriar G
SG
Vuorio
Eero
E
Bornstein
Paul
P
Penttinen
Risto
R
D000367:Age Factors; D000784:Aortic Dissection / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001019:Aortic Rupture / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D024022:Fibrillar Collagens / Q000648:ultrastructure; D006909:Hydroxyproline / Q000032:analysis; D007438:Introns; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D016019:Survival Analysis
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024022:Fibrillar Collagens; D012333:RNA, Messenger; D003094:Collagen; D006909:Hydroxyproline