Quantitative genetic basis of arterial phenotypes in the Brown Norway rat

Abstract

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.

Localization of genetic loci controlling hydronephrosis in the Brown Norway rat and its association with hematuria

“…We chose to use backcross (BC) rats [(BN ϫ LOU) ϫ BN] for this linkage study because the same rats were used to study genetic linkage of several arterial phenotypes exhibited by the BN (20). A backcross was more suited to the study of two of these phenotypes, rupture of the abdominal aortic internal elastic lamina (IEL) and persistent ductus arteriosus (PDA), than an intercross (F2).…”

Transcription Profiles of the Ductus Arteriosus in Brown-Norway Rats With Irregular Elastic Fiber Formation

“…6, 7 The BN rat also develops several elastin-related arterial impairments such as ruptures of the IEL in the abdominal aorta, and aortic elastin deficit in adults. 10 Therefore, these findings suggest that the inbred BN rat strain exhibits systemic elastin-related impairments that might cause PDA. The genetic or molecular mechanisms underlying elastin impairment and PDA phenotypes in this rat strain have not yet been fully investigated, although a study of a genome-wide scan with linkage analysis in BN rats reported that 2 different quantitative trait loci (QTL) on chromosomes 8 and 9 were significantly linked to PDA in this strain.…”

“…Kota et al reported that 2 different QTL on chromosomes 8 and 9 were significantly linked to PDA in this strain using a genomewide scan with linkage analysis in BN rats. 10 In this regard, Tbx20 (8q13), Scn3b (8q22), Stac (8q32), Sphkap (9q34), and Trpm8 (9q35) are the upregulated genes, and Rup2 (8q21), Slc37a2 (8q21), and RGD1561216 (8q22) are the downregulated genes in the DA of BN neonates located in chromosomes 8 and 9. Although none of them have been known to play a role in elastogenesis, these genes are of great interest as candidate genes responsible for the PDA phenotype in BN rats.…”

“…The genetic or molecular mechanisms underlying elastin impairment and PDA phenotypes in this rat strain have not yet been fully investigated, although a study of a genome-wide scan with linkage analysis in BN rats reported that 2 different quantitative trait loci (QTL) on chromosomes 8 and 9 were significantly linked to PDA in this strain. 10 Furthermore, our recent findings demonstrated that prostaglanding E2 (PGE2) and its receptor type 4 (EP4, or Ptger4) play a critical role in impaired elastogenesis of the DA via degradation of lysyl oxidase (Lox), a key enzyme that catalyzes elastin cross-links in DA SMCs, and that EP4 knockout mice displayed the arterialized PDA, 11 making EP4 as a possible candidate for the PDA phenotype of BN rats. In the present study, we investigated the transcription profiles of the BN rat DA at birth to understand the genetic and/or molecular mechanisms underlying the structural abnormalities, especially the irregular elastic fiber formation.…”

“…Furthermore, Kota et al demonstrated that the phenotype of thoracic aortic elastic content linked to 2 loci on chromosome 2 where the EP4 gene is located. 10 Therefore, EP4 and its related genes are also of great interest. Although there was no mutation or single nucleotid polymorphism in the coding region of the EP4 genome, we found that the PGE2-specific receptor, EP4, was significantly downregulated in the DA of BN neonates.…”