当前位置: X-MOL 学术Cell Rep. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy.
Cell Reports ( IF 7.5 ) Pub Date : 2020-09-08 , DOI: 10.1016/j.celrep.2020.108117
Francesca Briganti 1 , Han Sun 2 , Wu Wei 3 , Jingyan Wu 2 , Chenchen Zhu 2 , Martin Liss 4 , Ioannis Karakikes 5 , Shannon Rego 2 , Andrea Cipriano 6 , Michael Snyder 2 , Benjamin Meder 7 , Zhenyu Xu 8 , Gilles Millat 9 , Michael Gotthardt 10 , Mark Mercola 11 , Lars M Steinmetz 12
Affiliation  

Recent advances in induced pluripotent stem cell (iPSC) technology and directed differentiation of iPSCs into cardiomyocytes (iPSC-CMs) make it possible to model genetic heart disease in vitro. We apply CRISPR/Cas9 genome editing technology to introduce three RBM20 mutations in iPSCs and differentiate them into iPSC-CMs to establish an in vitro model of RBM20 mutant dilated cardiomyopathy (DCM). In iPSC-CMs harboring a known causal RBM20 variant, the splicing of RBM20 target genes, calcium handling, and contractility are impaired consistent with the disease manifestation in patients. A variant (Pro633Leu) identified by exome sequencing of patient genomes displays the same disease phenotypes, thus establishing this variant as disease causing. We find that all-trans retinoic acid upregulates RBM20 expression and reverts the splicing, calcium handling, and contractility defects in iPSC-CMs with different causal RBM20 mutations. These results suggest that pharmacological upregulation of RBM20 expression is a promising therapeutic strategy for DCM patients with a heterozygous mutation in RBM20.



中文翻译:

缺乏RBM20的DCM的iPSC建模将RBM20的上调确定为一种治疗策略。

诱导多能干细胞(iPSC)技术的最新进展以及将iPSC定向分化为心肌细胞(iPSC-CMs)使得在体外模拟遗传性心脏病成为可能。我们应用CRISPR / Cas9基因组编辑技术在iPSC中引入三个RBM20突变,并将它们分化为iPSC-CM,以建立RBM20突变型扩张型心肌病(DCM)的体外模型。在具有已知因果关系的RPS20的iPSC-CM中RBM20靶基因的剪接,钙处理和收缩力受损,与患者的疾病表现相符。通过患者基因组外显子组测序鉴定的变体(Pro633Leu)显示相同的疾病表型,因此将该变体确定为引起疾病的原因。我们发现全反式维甲酸可上调RBM20的表达,并恢复具有不同因果关系的RBM20突变的iPSC-CM中的剪接,钙处理和可收缩性缺陷。这些结果表明,RBM20表达的药理上调是DCM患者的杂合突变有希望的治疗策略RBM20

更新日期:2020-09-09
down
wechat
bug