The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest... more The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest, i.e., ruptures of the internal elastic lamina (RIEL) in the abdominal aorta (AA), iliac (IAs), and renal arteries, aortic elastin deficit and higher frequency of persistent ductus arteriosus (PDA) than other strains. We investigated the genetic basis of these phenotypes. We established a backcross between BN and the LOU reference strain and performed a genome-wide scan on 104 males and 105 females with 193 microsatellite markers followed by linkage analysis. RIEL in AA and IAs showed highly significant linkage to a locus on chromosome 5 and suggestive linkage to a locus on chromosome 10, which is syntenic to one linked to a syndrome of thoracic aortic aneurysms with PDA in humans. In contrast, renal artery RIEL mapped to a chromosome 3 locus and thoracic aortic elastic content to two loci on chromosome 2. PDA was significantly linked to two different quantitative trait loci (QTL) on chromosomes 8 and 9. This is the first study in rats to identify genetic loci for PDA. We identified 21 candidate genes by functional relevance or integration of our mapping data with global expression analysis. Sequencing these genes identified 47 single nucleotide polymorphisms, but no functionally relevant amino acid changes. By expression analysis, myosin heavy chain 10, nonmuscle, in the chromosome 10 QTL, emerged as a candidate for RIEL in AA and IAs. Furthermore, production of a congenic line for the chromosome 5 QTL proved implication of this locus in RIEL formation. internal elastic lamina; abdominal aorta; elastin; ductus arteriosus; quantitative trait loci THE INBRED BROWN NORWAY (BN) rat presents several interesting arterial phenotypes which are not observed in other common strains of laboratory rat. All BN rats develop spontaneously, during growth and aging, large numbers of ruptures in the internal elastic lamina (RIEL) in the abdominal aorta (AA) and the iliac arteries (IAs), whereas most other strains do not . Most strains develop a few RIEL in the renal artery and many in the caudal artery (26), but again, the BN is more affected than other strains, such as the Long Evans (LE) (5) and LOU (unpublished data). Although the formation of these RIEL may be influenced by many factors, including hemodynamic factors (27) and various compounds such as -aminopropionitrile (BAPN) (5) and inhibitors of the renin-angiotensin system (12), it is nevertheless strongly genetically deter-* L. Kota and M. Osborne-Pellegrin contributed equally to this work. Article published online before print. See web site for date of publication
The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest... more The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest, i.e., ruptures of the internal elastic lamina (RIEL) in the abdominal aorta (AA), iliac (IAs), and renal arteries, aortic elastin deficit and higher frequency of persistent ductus arteriosus (PDA) than other strains. We investigated the genetic basis of these phenotypes. We established a backcross between BN and the LOU reference strain and performed a genome-wide scan on 104 males and 105 females with 193 microsatellite markers followed by linkage analysis. RIEL in AA and IAs showed highly significant linkage to a locus on chromosome 5 and suggestive linkage to a locus on chromosome 10, which is syntenic to one linked to a syndrome of thoracic aortic aneurysms with PDA in humans. In contrast, renal artery RIEL mapped to a chromosome 3 locus and thoracic aortic elastic content to two loci on chromosome 2. PDA was significantly linked to two different quantitative trait loci (QTL) on chromosomes 8 and 9. This is the first study in rats to identify genetic loci for PDA. We identified 21 candidate genes by functional relevance or integration of our mapping data with global expression analysis. Sequencing these genes identified 47 single nucleotide polymorphisms, but no functionally relevant amino acid changes. By expression analysis, myosin heavy chain 10, nonmuscle, in the chromosome 10 QTL, emerged as a candidate for RIEL in AA and IAs. Furthermore, production of a congenic line for the chromosome 5 QTL proved implication of this locus in RIEL formation. internal elastic lamina; abdominal aorta; elastin; ductus arteriosus; quantitative trait loci THE INBRED BROWN NORWAY (BN) rat presents several interesting arterial phenotypes which are not observed in other common strains of laboratory rat. All BN rats develop spontaneously, during growth and aging, large numbers of ruptures in the internal elastic lamina (RIEL) in the abdominal aorta (AA) and the iliac arteries (IAs), whereas most other strains do not . Most strains develop a few RIEL in the renal artery and many in the caudal artery (26), but again, the BN is more affected than other strains, such as the Long Evans (LE) (5) and LOU (unpublished data). Although the formation of these RIEL may be influenced by many factors, including hemodynamic factors (27) and various compounds such as -aminopropionitrile (BAPN) (5) and inhibitors of the renin-angiotensin system (12), it is nevertheless strongly genetically deter-* L. Kota and M. Osborne-Pellegrin contributed equally to this work. Article published online before print. See web site for date of publication
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