RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium.
J Genet Genomics
; 51(5): 543-553, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38181896
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-rcan3ATG-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.
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Peixe-Zebra
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En
Ano de publicação:
2024
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Article