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

作　　者：Ting Hu Lan Liu He Wang Mei Yang Bocheng Xu Hanbing Xie Ziyuan Lin Xiaolei Jin Ping Wang Yanyan Liu Huaqin Sun Shanling Liu 

机构地区：[1]Department of Medical Genetics,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China [2]Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University),Ministry of Education,Chengdu,Sichuan 610041,China [3]Medical College,Tibet University,Lhasa,Tibet 850000,China [4]SCU-CUHK Joint Laboratory for Reproductive Medicine,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China [5]West China School of Medicine,Sichuan University,Chengdu,Sichuan 610041,China

出　　处：《Journal of Genetics and Genomics》2024年第5期543-553,共11页遗传学报（英文版）

基　　金：the National Key Research and Development Program of China(2022YFC2703302);the National Natural Science Foundation of China(82271692);the Sichuan Province Science and Technology Support Program,China(2022YFS0078);the Natural Science Foundation of Sichuan Province(2022NSFSC0782);the Fundamental Research Funds for the Central Universities(SCU2022F4080);Horizontal research project of Sichuan University(21H1095 and 21H1116).

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.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-rcan3^(ATG)-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.

关 键 词：CARDIOMYOPATHY NVM RCAN3 Mitochondrial structure Heartdefects 

分 类 号：R739.41[医药卫生—肿瘤]