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Abstract：
Titin truncating variants (TTNtvs) are the most common genetic cause of dilated cardiomyopathy (DCM). Among four regions of titin, A-band enrichment of DCM-causing TTNtvs is widely accepted but the underlying mechanism is still unknown. Meanwhile, few reports have identified exon 327 as a highly mutated A-band exon but the degree of exon 327 enrichment has not been quantitatively investigated. To find the real hotspot of DCM-causing TTNtvs, we aimed to reassess the degree of TTNtv enrichment in known titin regions and in exon 327, separately. In addition, we tried to explain exon 327 clustering in terms of nonsense-mediated mRNA decay (NMD) efficiency and a dominant negative mechanism recently proposed. Research papers focusing on TTNtvs found in patients with DCM were collected. A total of 612 patients with TTNtv-realated DCM were obtained from 10 studies. In the four regions of TTN and exon 327, the degree of TTNtvs enrichment was calculated in a way that the effect of distribution of highly expressed exons was normalized. As a result, exon 327 was the only region that showed significant enrichment for DCM-related TTNtv (p < .001). On the other hand, other A-band exons had almost the same number of TTNtv of random distribution. A review of RNAseq data revealed that the median allelic imbalance deviation of exon 327 TTNtvs was .04, indicating almost zero NMD. From these findings, we propose that the widely accepted A-band enrichment of DCM-related TTNtv is mostly attributable to exon 327 enrichment. In addition, based on the recently demonstrated dominant negative mechanism, the extremely low NMD efficiency seems to contribute to exon 327 enrichment.
摘要：
Titin截断变体（TTNTvs）是扩张型心肌病（DCM）最常见的遗传原因。在Titin的四个区域中，引起DCM的TTNTvs的A带富集已被广泛接受，但其潜在机制仍未知。同时,很少有报道确定外显子327为高度突变的A带外显子，但外显子327的富集程度尚未定量研究。为了找到引起DCM的TTNTvs的真正热点，我们旨在分别重新评估已知titin区域和外显子327中的TTNtv富集程度。此外,我们试图从无义介导的mRNA衰减（NMD）效率和最近提出的显性负机制来解释外显子327聚类。收集了针对DCM患者中发现的TTNTvs的研究论文。从10项研究中获得了612名患有TTNtv-realatedDCM的患者。在TTN和外显子327的四个区域中，以使高度表达的外显子的分布效应标准化的方式计算了TTNTvs的富集程度。因此,外显子327是唯一显示DCM相关TTNtv显著富集的区域(p<.001)。另一方面,其他A波段外显子具有几乎相同数量的随机分布的TTNtv。对RNAseq数据的审查显示，外显子327TTNTvs的等位基因不平衡偏差中位数为0.04，表明NMD几乎为零。从这些发现中,我们认为，DCM相关的TTNtv的A波段富集被广泛接受主要归因于外显子327富集。此外,基于最近证明的显性消极机制，极低的NMD效率似乎有助于外显子327的富集。
