Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat.
The inbred Brown Norway (BN) rat develops spontaneous ruptures of the internal elastic lamina (RIEL) of the abdominal aorta (AA) and iliac arteries. Prior studies with crosses of the BN/Orl RJ (susceptible) and LOU/M (resistant) showed the presence of a significant QTL on chromosome 5 and the production of congenic rats proved the involvement of this locus. In this study, we further dissected the above-mentioned QTL by creating a new panel of LOU.BN(chr5) congenic and subcongenic lines and reduced the locus to 5.2 Mb. Then we studied 1,002 heterogeneous stock (HS) rats, whose phenotyping revealed a low prevalence and high variability for RIEL. High-resolution mapping in the HS panel detected the major locus on chromosome 5 (log P > 35) and refined it to 1.4 Mb. Subsequently, RNA-seq analysis on AA of BN, congenics, and LOU revealed expression differences for only protease inhibitor 15 (Pi15) gene and a putative long intergenic noncoding RNA (lincRNA) within the linkage region. The high abundance of lincRNA with respect to reduced Pi15 expression, in conjunction with exertion of longitudinal strain, may be related to RIEL, indicating the potential importance of proteases in biological processes related to defective aortic internal elastic lamina structure. Similar mechanisms may be involved in aneurysm initiation in the human AA.
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
Samreen
S
Falak
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
Sebastian
S
Schafer
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
Amelie
A
Baud
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
Oliver
O
Hummel
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
Herbert
H
Schulz
Institute of Cardiometabolism and Nutrition, University Pierre & Marie Curie, Hospital Pitié Salpetrière, Paris, France; and.
Dominique
D
Gauguier
Max Delbrück Center for Molecular Medicine, Berlin, Germany; nhuebner@mdc-berlin.de.
Norbert
N
Hubner
Inserm U698-University Paris 7, Hôpital Bichat, Paris, France.
Mary
M
Osborne-Pellegrin
D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology*; D001019:Aortic Rupture / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D004547:Elastic Tissue / Q000473:pathology; D005260:Female; D008297:Male; D020641:Polymorphism, Single Nucleotide; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci; D062085:RNA, Long Noncoding; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains
C000597781:Pi15 protein, rat; D053491:Proteinase Inhibitory Proteins, Secretory; D062085:RNA, Long Noncoding; D000629:Aminopropionitrile
heterogeneous stock; protease inhibitor 15; rupture of the internal elastic lamina; subcongenics