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

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

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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.

CardiomyopathyNVMRCAN3Mitochondrial structureHeart defects

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

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Department of Medical Genetics,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China

Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University),Ministry of Education,Chengdu,Sichuan 610041,China

Medical College,Tibet University,Lhasa,Tibet 850000,China

SCU-CUHK Joint Laboratory for Reproductive Medicine,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China

West China School of Medicine,Sichuan University,Chengdu,Sichuan 610041,China

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国家重点研发计划国家自然科学基金Sichuan Province Science and Technology Support Program,China四川省自然科学基金中央高校基本科研业务费专项Horizontal research project of Sichuan UniversityHorizontal research project of Sichuan University

2022YFC2703302822716922022YFS00782022NSFSC0782SCU2022F408021H109521H1116

2024

10.1016/j.jgg.2023.12.010

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(5)
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