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Genetic and functional implications of an exonic TRIM55 variant in heart failure.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.yjmcc.2019.12.008 Juho Heliste 1 , Himanshu Chheda 2 , Ilkka Paatero 3 , Tiina A Salminen 4 , Yevhen Akimov 2 , Jere Paavola 5 , Klaus Elenius 6 , Tero Aittokallio 7
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.yjmcc.2019.12.008 Juho Heliste 1 , Himanshu Chheda 2 , Ilkka Paatero 3 , Tiina A Salminen 4 , Yevhen Akimov 2 , Jere Paavola 5 , Klaus Elenius 6 , Tero Aittokallio 7
Affiliation
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BACKGROUND
To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant in vitro and in vivo.
METHODS AND RESULTS
Heart failure-associated variants were screened in genotyping array data of the FINRISK study, consisting of 994 cases and 20,118 controls. Based on logistic regression analysis, a potentially damaging variant in TRIM55 (rs138811034), encoding an E140K variant, was selected for validations. In HL-1 cardiomyocytes, we used CRISPR/Cas9 technology to introduce the variant in the endogenous locus, and additionally TRIM55 wildtype or E140K was overexpressed from plasmid. Functional responses were profiled using whole-genome RNA sequencing, RT-PCR and Western analyses, cell viability and cell cycle assays and cell surface area measurements. In zebrafish embryos, cardiac contractility was measured using videomicroscopy after CRISPR-mediated knockout of trim55a or plasmid overexpression of TRIM55 WT or E140K. Genes related to muscle contraction and cardiac stress were highly regulated in Trim55 E140K/- cardiomyocytes. When compared to the WT/WT cells, the variant cells demonstrated reduced viability, significant hypertrophic response to isoproterenol, p21 protein overexpression and impaired cell cycle progression. In zebrafish embryos, the deletion of trim55a or overexpression of TRIM55 E140K reduced cardiac contractility as compared to embryos with wildtype genotype or overexpression of WT TRIM55, respectively.
CONCLUSIONS
A previously uncharacterized TRIM55 E140K variant demonstrated a number of functional implications for cardiomyocyte functions in vitro and in vivo. These findings suggest a novel role for TRIM55 polymorphism in predisposing to heart failure.
中文翻译：
心脏衰竭中外显子TRIM55变体的遗传和功能含义。
背景技术为了解决散发性心力衰竭的缺失遗传性，我们筛选了芬兰人群中与心力衰竭相关的新型遗传变异体，并在功能上表征了体内和体外的新型变异体。方法和结果在FINRISK研究的基因分型阵列数据中筛选了与心力衰竭相关的变异体，其中包括994例病例和20,118例对照。基于逻辑回归分析，选择了编码E140K变体的TRIM55（rs138811034）中具有潜在破坏性的变体进行验证。在HL-1心肌细胞中，我们使用CRISPR / Cas9技术将变异体引入内源性基因座，另外从质粒中过表达了TRIM55野生型或E140K。使用全基因组RNA测序，RT-PCR和Western分析对功能性反应进行了分析，细胞活力和细胞周期测定以及细胞表面积测量。在斑马鱼胚胎中，在CRISPR介导的trim55a敲除或TRIM55 WT或E140K质粒过表达后，使用视频显微镜测量了心脏收缩力。在Trim55 E140K /-心肌细胞中，与肌肉收缩和心脏压力有关的基因受到高度调节。当与WT / WT细胞相比时，变异细胞表现出活力降低，对异丙肾上腺素的明显肥大反应，p21蛋白过表达和细胞周期进程受损。在斑马鱼胚胎中，与野生型基因型或野生型WT TRIM55的胚胎相比，trim55a的缺失或TRIM55 E140K的过表达降低了心脏的收缩力。结论以前未鉴定的TRIM55 E140K变体在体外和体内对心肌细胞功能表现出许多功能含义。这些发现表明，TRIM55基因多态性在诱发心力衰竭中具有新的作用。
更新日期：2019-12-19
中文翻译：
心脏衰竭中外显子TRIM55变体的遗传和功能含义。
背景技术为了解决散发性心力衰竭的缺失遗传性，我们筛选了芬兰人群中与心力衰竭相关的新型遗传变异体，并在功能上表征了体内和体外的新型变异体。方法和结果在FINRISK研究的基因分型阵列数据中筛选了与心力衰竭相关的变异体，其中包括994例病例和20,118例对照。基于逻辑回归分析，选择了编码E140K变体的TRIM55（rs138811034）中具有潜在破坏性的变体进行验证。在HL-1心肌细胞中，我们使用CRISPR / Cas9技术将变异体引入内源性基因座，另外从质粒中过表达了TRIM55野生型或E140K。使用全基因组RNA测序，RT-PCR和Western分析对功能性反应进行了分析，细胞活力和细胞周期测定以及细胞表面积测量。在斑马鱼胚胎中，在CRISPR介导的trim55a敲除或TRIM55 WT或E140K质粒过表达后，使用视频显微镜测量了心脏收缩力。在Trim55 E140K /-心肌细胞中，与肌肉收缩和心脏压力有关的基因受到高度调节。当与WT / WT细胞相比时，变异细胞表现出活力降低，对异丙肾上腺素的明显肥大反应，p21蛋白过表达和细胞周期进程受损。在斑马鱼胚胎中，与野生型基因型或野生型WT TRIM55的胚胎相比，trim55a的缺失或TRIM55 E140K的过表达降低了心脏的收缩力。结论以前未鉴定的TRIM55 E140K变体在体外和体内对心肌细胞功能表现出许多功能含义。这些发现表明，TRIM55基因多态性在诱发心力衰竭中具有新的作用。
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