I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy.
I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy.
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DOI：
10.1007/s00109-022-02262-8
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发表时间：
2022-12
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RBM 20是扩张型心肌病（DCM）的易感基因之一。RS结构域的变异已在许多DCM患者中报道，但RNA识别基序内的变异的致病性仍然未知。在猝死队列中鉴定了两名具有I536 T-RBM 20变体但没有明显DCM表型的人类患者。进行剪接报告基因测定，并产生I538 T敲入小鼠模型（Rbm 20 I538 T）以确定该变体的显著性。报告基因测定表明，与野生型相比，人I536 T变体影响TTN剪接模式。在小鼠实验中，Rbm 20 I538 T小鼠在Ttn、Ldb 3、Camk 2d和Ryr 2中显示出不同的剪接模式。Rbm 20 I538 T小鼠心肌组织中Casq 1、Mybpc 2和Myot表达上调，但组织病理学检查和超声心动图检查均未发现DCM和心功能不全。I536 T-RBM 20（I538 T-Rbm 20）变体改变基因剪接并影响基因表达，但Ttn和Ca处理基因（如Casq 1、Camk 2d和Ryr 2）的剪接和表达变化不会导致小鼠模型中的DCM形态。·鉴定了两名具有I536 T-RBM 20变体而没有DCM表型的人类患者。·剪接报告基因测定证明该变体影响TTN剪接。·Rbm 20 I538 T小鼠既未显示DCM也未显示心脏功能障碍。·Rbm 20 I538 T小鼠表现出不同的剪接模式和基因表达。在线版本包含补充材料，可通过10.1007/s 00109 -022-02262-8获得。
RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-RBM20 variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (Rbm20I538T) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected the TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice showed different splicing patterns in Ttn, Ldb3, Camk2d, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were upregulated in Rbm20I538T mice, but Rbm20I538T mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d, and Ryr2 do not cause DCM morphology in the mouse model. • Two human patients with the I536T-RBM20 variant without a DCM phenotype were identified. • A splicing reporter assay demonstrated that the variant affected the TTN splicing. • Rbm20I538T mice showed neither DCM nor cardiac dysfunction. • Rbm20I538T mice showed different splicing patterns and the gene expressions. The online version contains supplementary material available at 10.1007/s00109-022-02262-8.