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首页> 外文期刊>Circulation. Genomic and precision medicine. >MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene
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MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene

机译：mra变异导致心肌细胞肥大不同的诱导多功能干细胞心肌细胞细胞衍生更多的证据mra作为明确的努南Syndrome-Susceptibility基因

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BACKGROUND: MRAS was identified recently as a novel Noonan syndrome (NS)-susceptibility gene. Phenotypically, both patients with NS, harboring pathogenic MRAS variants, displayed severe cardiac hypertrophy. This study aimed to demonstrate both the necessity and sufficiency of a patient-specific variant (p.Gly23Val-MRAS) to cause NS through the generation and characterization of patient-specific, isogenic control, and disease modeled induced pluripotent stem cell (iPSC) lines. METHODS: iPSCs were derived from a patient with a p.Gly23Val-MRAS variant to assess the effect of MRAS variants on pathogenesis of NS-associated cardiac hypertrophy. CRISPR/Cas9 gene editing was used to correct the pathogenic p.Gly23Val-MRAS variant in patient cells (isogenic control) and to introduce the pathogenic variant into unrelated control cells (disease modeled) to determine the necessity and sufficiency of the p.Gly23Val-MRAS variant to elicit the disease phenotype in iPSC-derived cardiomyocytes (iPSC-CMs). iPSC-CMs were analyzed by microscopy and immunofluroesence, single-cell RNAseq, Western blot, room temperature-quantitative polymerase chain reaction, and live-cell calcium imaging to define an in vitro phenotype of MRAS-mediated cardiac hypertrophy. RESULTS: Compared with controls, both patient and disease modeled iPSC-CMs were significantly larger and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca2+ handling, including increased frequency of irregular Ca2+ transients and changes in Ca2+ handling kinetics. CONCLUSIONS: p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac hypertrophy phenotype in iPSC-CMs that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling-providing further evidence to establish the monogenetic pathogenicity of p.Gly23Val-MRAS in NS with cardiac hypertrophy.
机译：背景:mra最近被确定为小说努南综合症(NS)易感性基因。NS患者表型,窝藏致病性mra变异,显示严重心脏肥大。证明的必要性和充分性一个特定的变体(p.Gly23Val-MRAS)因为通过生成和NS描述的患者,同基因的疾病控制和诱导多功能建模干细胞(iPSC)线。p.Gly23Val-MRAS源自一个病人变体评估mra变异的影响发病机理的NS-associated心脏肥大。纠正致病p.Gly23Val-MRAS变体病人细胞(同基因的控制)和介绍致病性变异成不相关的控制细胞(疾病模型)来确定p.Gly23Val-MRAS的必要性和充分性引起疾病的表型变异iPSC-derived心肌细胞(iPSC-CMs)。分析了通过显微镜和单细胞RNAseq immunofluroesence,西方吸干,房间temperature-quantitative聚合酶连锁反应,live-cell钙成像定义一个体外MRAS-mediated表型心脏肥大。控制,病人和疾病建模iPSC-CMs明显更大证明了基因表达的变化细胞内途径信号的特征心脏肥大。疾病建模iPSC-CMs显示Ca2 +受损处理,包括增加的频率不规则的Ca2 +瞬变和Ca2 +的变化处理动力学。既是必要的,足以引起心脏肥大在iPSC-CMs表型包括细胞大小,增加心脏的变化基因表达和异常的钙handling-providing建立进一步证据p.Gly23Val-MRAS的无性生殖的致病性在NS心脏肥大。

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