Abstract：
Noncompaction of the ventricular myocardium (NVM), the third most diagnosed cardiomyopathy, is characterized by prominent trabeculae and intratrabecular recesses. However, the genetic etiology of 40%-60% of NVM cases remains unknown. Here, we identify two infants with NVM, in a nonconsanguineous family, with a typical clinical presentation of persistent bradycardia since the prenatal period. A homozygous missense variant (R223L) of RCAN family member 3 (RCAN3) is detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction is detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan-/- embryos. Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNAs rescue these phenotypes. RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency results in reduced proliferation and increased apoptosis, together with an abnormal mitochondrial ultrastructure. Thus, we suggest that RCAN3 is a susceptibility gene for cardiomyopathies, especially NVM and that the R223L mutation is a potential loss-of-function variant.
摘要：
心肌致密化不全(NVM),第三大被诊断为心肌病，以突出的小梁和分子内凹陷为特征。然而,40-60%的NVM病例的遗传病因仍然未知.我们确定了两名患有NVM的婴儿，在一个没有血缘关系的家庭里,有产前持续心动过缓的典型临床表现。使用全外显子组测序在两个婴儿中检测到RCAN家族成员3(RCAN3)的纯合错义变体(R223L)。在斑马鱼模型中,在rcan3缺乏症(注射MO-rcan3ATG)和rcan-/-胚胎中检测到显著的心功能不全。在缺乏rcan3的胚胎中还检测到心内膜和心肌层的发育异常。RCAN3R223L变异mRNA不能挽救由rcan3敲低或敲除引起的心脏缺陷；然而，hRCAN3mRNA拯救了这些表型。RNA-seq实验表明，在rcan3敲低斑马鱼模型中，参与心肌病的几个基因通过多个信号通路受到显著调控。在人类心肌细胞中，RCAN3缺乏导致增殖减少和凋亡增加，线粒体超微结构异常.因此，我们认为RCAN3是心肌病的易感基因，尤其是NVM，R223L突变是一种潜在的功能丧失变异。
