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Polymorphisms of CSF1R and WISP1 genes are associated with severity of familial adenomatous polyposis in APC1311 pigs.
Gene ( IF 3.5 ) Pub Date : 2020-07-25 , DOI: 10.1016/j.gene.2020.144988
Agata Sikorska 1 , Monika Stachowiak 1 , Tatiana Flisikowska 2 , Joanna Stachecka 1 , Krzysztof Flisikowski 2 , Marek Switonski 1
Affiliation  

Hereditary familial adenomatous polyposis (FAP) in humans significantly increases the risk of development of colorectal cancer (CRC). Germline mutations in the APC (adenomatous polyposis coli) gene are responsible for FAP. Despite having the same causative mutation, the severity of the disease differs from patient to patient. The porcine FAP model carrying a truncating APC1311 mutation, orthologous to the dominant human mutation that leads to severe form of the disease (APC1309), mirrors the severity of polyposis. Earlier RNAseq studies have revealed the differential expression of WISP1 and CSF1R in samples derived from low-grade (LG-IEN) and more advanced high-grade (HG-IEN) colon polyps of APC1311/+ pigs. The grade of dysplasia was correlated with the severity of polyposis in APC1311/+ pigs characterized by a low (LP) and high (HP) numbers of polyps. The goal of this work was to find DNA variants that regulate the expression of CSF1R and WISP1 in LP and HP pigs. In total, 32 and 36 polymorphisms in CSF1R and WISP1 were found, respectively. Of these, the genotype frequency of four silent SNPs in the coding region of WISP1 differed significantly between LP and HP lines. In silico analysis revealed an elevated minimum free energy (MFE) for three of these SNPs, suggesting their role in mRNA structure stability. Furthermore, four polymorphisms in the promoter region of CSF1R, cosegregating as a common haplotype, were associated with polyp number in APC1311/+ pigs. A secreted alkaline phosphatase (SEAP) assay showed, however, that these variants have no direct effect on the activity of the CSF1R promoter. Concluding, our study identified polymorphisms in CSF1R and WISP1 that are potentially associated with the severity of polyposis in APC1311/+ pigs.



中文翻译:

CSF1R和WISP1基因的多态性与APC1311猪的家族性腺瘤性息肉病的严重程度有关。

人的遗传性家族性腺瘤性息肉病(FAP)大大增加了结直肠癌(CRC)发生的风险。在种系突变APC(腺瘤性结肠息肉病)基因是负责FAP。尽管具有相同的致病突变,但疾病的严重程度因患者而异。携带截短的APC 1311突变的猪FAP模型与导致疾病严重形式的人类主要突变(APC 1309)是直系同源的,反映了息肉病的严重性。早期的RNAseq研究表明WISP1CSF1R的差异表达APC 1311 / +猪的低度(LG-IEN)和更高级的高度(HG-IEN)结肠息肉中提取的样品。发育不良的程度与APC 1311 / +猪的息肉病严重程度相关,其特征是息肉数量低(LP)高(HP)。这项工作的目的是找到调节LP和HP猪中CSF1RWISP1表达的DNA变体。总共在CSF1RWISP1中分别发现了32和36个多态性。其中,WISP1编码区中的四个沉默SNP的基因型频率在LP和HP品系之间显着不同。电脑分析显示,其中三个SNP的最低自由能(MFE)升高,表明它们在mRNA结构稳定性中的作用。此外,CSF1R启动子区域的四个多态性作为共同的单倍型共分离,与APC 1311 / +猪的息肉数目有关。但是,分泌的碱性磷酸酶(SEAP)分析表明,这些变体对CSF1R启动子的活性没有直接影响。最后,我们的研究确定了CSF1RWISP1中的多态性可能与APC 1311 / +猪的息肉病严重程度有关。

更新日期:2020-07-31
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