<i>RCAN</i> family member 3 deficiency contributes to noncompaction of the ventricular myocardium

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

doi:10.1016/j.jgg.2023.12.010

Volume 51 Issue 5

May 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(5): 543-553

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

doi: 10.1016/j.jgg.2023.12.010

Ting Hu^a,b,
Lan Liu^a,c,
He Wang^a,b,
Mei Yang^a,b,
Bocheng Xu^a,b,
Hanbing Xie^a,b,
Ziyuan Lin^b,d,
Xiaolei Jin^a,b,e,
Ping Wang^a,b,
Yanyan Liu^a,b,
Huaqin Sun^b,d,
Shanling Liu^a,b

a. Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
b. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, China;
c. Medical College, Tibet University, Lhasa, Tibet 850000, China;
d. SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
e. West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China

Funds:

This study was supported by 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), and Horizontal research project of Sichuan University (21H1095 and 21H1116).

Received Date: 2023-12-28
Accepted Date: 2023-12-28

Available Online: 2025-06-06

Publish Date: 2024-01-03

Abstract

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 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.
- Cardiomyopathy,
- NVM,
- RCAN3,
- Mitochondrial structure,
- Heart defects

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References(47)

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