Falak Samreen, Schafer Sebastian, Baud Amelie, Hummel Oliver, Schulz Herbert, Gauguier Dominique, Hubner Norbert, Osborne-Pellegrin Mary
Max Delbrück Center for Molecular Medicine, Berlin, Germany;
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
Physiol Genomics. 2014 Jun 15;46(12):418-28. doi: 10.1152/physiolgenomics.00004.2014. Epub 2014 May 1.
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.
近交系棕色挪威（BN）大鼠会出现腹主动脉（AA）和髂动脉内弹性膜（RIEL）的自发性破裂。先前对BN/Orl RJ（易感）和LOU/M（抗性）杂交后代的研究表明，5号染色体上存在一个显著的数量性状基因座（QTL），培育近交系大鼠证明了该基因座的作用。在本研究中，我们通过创建一组新的LOU.BN（chr5）近交系和亚近交系进一步剖析上述QTL，并将该基因座缩小至5.2 Mb。然后我们研究了1002只异质群体（HS）大鼠，其表型分析显示RIEL的患病率较低且变异性较高。在HS群体中进行的高分辨率定位检测到5号染色体上的主要基因座（对数P>35），并将其精确定位到1.4 Mb。随后，对BN、近交系和LOU的AA进行RNA测序分析，结果显示仅在连锁区域内的蛋白酶抑制剂15（Pi15）基因和一个假定的长链基因间非编码RNA（lincRNA）存在表达差异。相对于降低的Pi15表达，lincRNA的高丰度，再加上纵向应变的作用，可能与RIEL有关，这表明蛋白酶在与主动脉内弹性膜结构缺陷相关的生物学过程中具有潜在重要性。类似的机制可能也参与了人类AA中动脉瘤的起始过程。
