PUBLICATION
RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium
- Authors
- Hu, T., Liu, L., Wang, H., Yang, M., Xu, B., Xie, H., Lin, Z., Jin, X., Wang, P., Liu, Y., Sun, H., Liu, S.
- ID
- ZDB-PUB-240107-4
- Date
- 2024
- Source
- Journal of genetics and genomics = Yi chuan xue bao 51(5): 543-553 (Journal)
- Registered Authors
- Sun, Huaqin, Wang, Ping
- Keywords
- Cardiomyopathy, Heart defects, Mitochondrial structure, NVM, RCAN3
- MeSH Terms
-
- Animals
- Cardiomyopathies/genetics
- Cardiomyopathies/pathology
- Exome Sequencing
- Female
- Heart Ventricles/pathology
- Humans
- Infant
- Isolated Noncompaction of the Ventricular Myocardium/genetics
- Isolated Noncompaction of the Ventricular Myocardium/pathology
- Male
- Mutation, Missense/genetics
- Myocardium/metabolism
- Myocardium/pathology
- Myocardium/ultrastructure
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Pedigree
- Zebrafish*/genetics
- PubMed
- 38181896 Full text @ J. Genet. Genomics
Citation
Hu, T., Liu, L., Wang, H., Yang, M., Xu, B., Xie, H., Lin, Z., Jin, X., Wang, P., Liu, Y., Sun, H., Liu, S. (2024) RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium. Journal of genetics and genomics = Yi chuan xue bao. 51(5):543-553.
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. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping