Analysis of TTN truncating variants (TTNtv) as a common cause of dilated cardiomyopathy (DCM)

TTN truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). However, we also observe potentially silent truncations in cardiac TTN transcripts in more than 0.5% of the general population, perhaps reflecting position-dependent allelic effects. To better understand TTNtv we integrated TTN allelic series, cardiac imaging and genomic data from humans and studied rat models with disparate TTNtv. In patients, TTNtv throughout the molecule, from the Z-disc to the M-line, were consistently associated with DCM. Ribosomal profiling in rat exposed the translational footprint of premature stop codons in Ttn and revealed TTNtv position-independent triggering of nonsense-mediated degradation of the mutant allele and a perturbation of cardiac metabolism. Changes in cardiac physiology were mild but upon stress the hearts of TTNtv rats failed. In healthy humans, TTNtv were associated with imaging precursors of DCM. TTNtv exhibit penetrant molecular and physiological phenotypes across species, with a continuum of expressivity in health and disease.

肌联蛋白截短变异体（TTN truncating variants，TTNtv）通常可引发扩张型心肌病（dilated cardiomyopathy，DCM）。然而，我们在超过0.5%的普通人群的心脏TTN转录本中观测到潜在的沉默截短变异，这一现象或可反映位置依赖性等位基因效应。为深入解析TTNtv，我们整合了人类的TTN等位基因系列、心脏影像学数据与基因组数据，并对携带不同TTNtv的大鼠模型开展研究。在患者队列中，贯穿整个肌联蛋白分子（从Z盘（Z-disc）至M线（M-line））的TTNtv均与DCM显著相关。针对大鼠的核糖体谱分析（ribosomal profiling）揭示了Ttn基因中提前终止密码子的翻译足迹，并证实TTNtv可不依赖位置触发突变等位基因的无义介导降解，同时干扰心脏代谢稳态。心脏生理学改变较为轻微，但当施加应激刺激时，携带TTNtv的大鼠心脏会出现功能衰竭。在健康个体中，TTNtv与DCM的影像学前驱表现相关联。TTNtv在多个物种中均表现出外显的分子与生理表型，在健康与疾病状态下呈现连续的表达谱。