四川大学Shanling Liu等研究人员合作发现，RCAN家族成员3缺乏症导致心室心肌致密化不全。2024年1月3日，国际学术期刊《遗传学报》在线发表了这一成果。

研究人员在一个非血缘家族中发现了两名患有心室心肌致密化不全（NVM）的婴儿，其典型临床表现是自出生前就出现持续性心动过缓。通过全外显子组测序，研究人员在这两名婴儿体内发现了RCAN家族成员3（RCAN3）的同位错义变体（R223L）。在斑马鱼模型中，研究人员发现rcan3缺乏（注射MO-rcan3^ATG）和rcan^-/-胚胎有明显的心脏功能障碍。在rcan3缺陷的胚胎中还检测到心内膜和心肌层发育不良。RCAN3 R223L变体mRNA不能挽救rcan3基因敲除或基因敲除导致的心脏缺陷；然而，hRCAN3 mRNA能挽救这些表型。

RNA-seq实验表明，在rcan3基因敲除的斑马鱼模型中，多个参与心肌病变的基因通过多种信号通路受到显著调控。在人类心肌细胞中，缺乏RCAN3会导致增殖减少、凋亡增加以及线粒体超微结构异常。因此，研究人员认为RCAN3是心肌病（尤其是NVM）的易感基因，而R223L突变是一种潜在的功能缺失变异。

据介绍，NVM是第三大确诊心肌病，其特征是突出的小梁和小梁内凹陷。然而，40%-60%的NVM病例的遗传病因仍然不明。

附：英文原文

Title: RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium

Author: anonymous

Issue&Volume: 2024/01/03

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. We identified 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) was detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction was detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan/ embryos. Developmental dysplasia of both endocardial and myocardial layers was also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs did not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNA rescued these phenotypes. RNA-seq experiments showed that several genes involved in cardiomyopathies were significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency resulted 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.

DOI: 10.1016/j.jgg.2023.12.010

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852723002679