基因敲除
斑马鱼
错义突变
生物
表型
心肌病
外显子组测序
突变
癌症研究
吗啉
室致密化不全
遗传学
内科学
细胞生物学
基因
内分泌学
心力衰竭
医学
作者
Ting Hu,Lan Liu,He Wang,Mei Yang,Bocheng Xu,Hong Xie,Ziyuan Lin,Xiaolei Jin,Ping Wang,Yanyan Liu,Huaqin Sun,Shanling Liu
标识
DOI:10.1016/j.jgg.2023.12.010
摘要
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.
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