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
  • Heart Ventricles/pathology
  • Female
  • Infant
  • Zebrafish*/genetics
  • Exome Sequencing
  • Isolated Noncompaction of the Ventricular Myocardium/genetics
  • Isolated Noncompaction of the Ventricular Myocardium/pathology
  • Myocardium/metabolism
  • Myocardium/pathology
  • Myocardium/ultrastructure
  • Male
  • Animals
  • Pedigree
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/pathology
  • Humans
  • Mutation, Missense/genetics
  • Cardiomyopathies/genetics
  • Cardiomyopathies/pathology
(all 19)
PubMed
38181896 Full text @ J. Genet. Genomics
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
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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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.