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 homozy-gous 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 myocar-dial 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.
基金项目
国家重点研发计划(2022YFC2703302)
国家自然科学基金(82271692)
Sichuan Province Science and Technology Support Program,China(2022YFS0078)
四川省自然科学基金(2022NSFSC0782)
中央高校基本科研业务费专项(SCU2022F4080)
Horizontal research project of Sichuan University(21H1095)
Horizontal research project of Sichuan University(21H1116)
NETL
NSTL
万方数据