PDF(Pubmed)
Abstract：
Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.
摘要：
对大规模人类基因组数据的分析已经产生了无法解释的突变，已知这些突变会导致健康个体的严重疾病。这里,我们报告了一个罕见的显性致死突变的意外恢复TPM1，肌节肌动蛋白结合蛋白，在一个五代系谱中，有八个患有大房间隔缺损（ASD）的个体。具有Tpm1突变的小鼠表现出早期胚胎致死性，肌原纤维组装被破坏，没有心跳。然而,患者诱导的多能干细胞衍生的心肌细胞显示正常搏动，伴有轻度肌丝缺陷，表明疾病抑制。另一种肌丝肌动蛋白结合蛋白TLN2的变体，被识别为候选抑制器。TLN2和TPM1变体的小鼠CRISPR敲入（KI）可以挽救心脏跳动，近期胎儿表现出大量ASD。因此，TPM1在ASD发病机制中的作用随着保护性TLN2变体抑制其胚胎致死率而展开。这些发现提供了证据，表明遗传弹性可以随着有害突变的遗传抑制而产生。
