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Abstract P2036: Induced Pluripotent Stem Cell- Derived Cardiomyocytes Provide New Insights Of The Pathogenic Consequences Of The Novel Frameshift Variant (c.5769delG) In MYH7 Gene
Abstract only Background: the genetic basis of hypertrophic cardiomyopathy is pleiotropic; A novel disease causing frameshift variant (c.5769delG, MYH7 ) in the beta-myosin heavy chain gene has been recently described. However, the mechanisms involved have not been adequately defined. We have used i...
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Published in: | Circulation research 2023-08, Vol.133 (Suppl_1) |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Abstract only
Background:
the genetic basis of hypertrophic cardiomyopathy is pleiotropic; A novel disease causing frameshift variant (c.5769delG,
MYH7
) in the beta-myosin heavy chain gene has been recently described. However, the mechanisms involved have not been adequately defined. We have used iPSC-CMs to investigate the underlying mechanisms.
Methods:
We have generated patient-specific iPSCs from clinically and genetically defined HCM patients carrying the pathogenic variant (c.5769delG) (n=3) and compared them to iPSCs from healthy controls (n=3). Optical mapping of calcium transients and cell action potential were performed under different stimulation conditions. iPSC-CMs contractility was recorded via widefield microscopy. Gene and protein expression analyses were performed using RT-PCR, immunoblotting and immunocytochemistry. RNA sequencing data from patients’ myocardial tissues was analyzed to validate gene expression data from iPSC-CMs.
Results:
HCM iPSCs-CMs showed a significant decrease in calcium release duration (i.e., time to peak) with decrease in calcium transient amplitude, compared to controls. This was associated with an accelerated contraction and a decreased contraction amplitude. Nonetheless, action potential analysis showed no significant changes. Transcriptome analysis of iPSC-CMs and patients’ myocardial tissues showed a significant down regulation of SERCA/ATP2A2
, MYH6
and
KCNIP2
.
Conclusion:
iPSC-CMs provided new insights of the pathogenic consequences of the novel variant in MYH7 gene on calcium handling and contractility.
Key words:
Hypertrophic Cardiomyopathy, Disease model,
MYH7
, iPSC-CMs, Calcium Handling, Contractility. |
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ISSN: | 0009-7330 1524-4571 |
DOI: | 10.1161/res.133.suppl_1.P2036 |