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Published on: August 8, 2022
A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of
Timon Seeger1,2, Rajani Shrestha1,2, Chi Keung Lam1,2
1Stanford Cardiovascular Institute (T.S., R.S., C.K.L., C.C., W.L.M., E.L., A.W., M.G, J.L., A.O., S.L., H.Y., M.M., M.W., E.A.A., I.K., J.C.W.), Stanford University School of Medicine, CA.
Insights
Mutations in MYBPC3 cause hypertrophic cardiomyopathy (HCM) by activating nonsense-mediated decay, leading to aberrant calcium handling in heart cells. Inhibiting this pathway normalized cardiac function in patient-derived cells.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Molecular Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is often caused by MYBPC3 mutations leading to premature termination codons (PTCs).
- The precise mechanisms by which MYBPC3 PTC mutations induce HCM remain unclear.
- This study investigates the molecular pathogenesis of HCM linked to MYBPC3 PTC mutations using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Purpose of the Study:
- To elucidate the molecular mechanisms underlying HCM pathogenesis in MYBPC3 PTC mutation carriers.
- To investigate the role of aberrant calcium handling and gene expression in HCM development.
- To determine the contribution of MYBPC3 haploinsufficiency to HCM.
Main Methods:
- Generation of isogenic iPSC lines from HCM patients with MYBPC3 PTC mutations via genome editing.
- Comprehensive phenotypic and transcriptome analyses of iPSC-CMs.
- Investigation of the nonsense-mediated decay (NMD) pathway's role and therapeutic inhibition.
Main Results:
- HCM iPSC-CMs exhibited abnormal calcium handling with prolonged decay and elevated diastolic calcium, without structural or contractile deficits.
- Reduced MYBPC3 mRNA but comparable protein levels indicated no significant MYBPC3 haploinsufficiency.
- Nonsense-mediated decay pathway activation and dysregulated cardiac gene expression were observed, constituting an in vitro HCM signature.
- Inhibition of NMD reversed molecular phenotypes and normalized calcium handling.
Conclusions:
- MYBPC3 PTC mutations in iPSC-CMs cause aberrant calcium signaling and molecular dysregulation independent of MYBPC3 haploinsufficiency.
- This study provides the first evidence directly linking chronic activation of the nonsense-mediated decay pathway to HCM development.
- Targeting the NMD pathway offers a potential therapeutic strategy for HCM.
Background:
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Methods:
Isogenic iPSC lines were generated from HCM patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing. Comprehensive phenotypic and transcriptome analyses were performed in the iPSC-CMs.
Results:
We observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in the absence of structural abnormalities or contracile dysfunction in HCM iPSC-CMs as compared to isogenic controls. The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the nonsense-mediated decay pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium-handling abnormalities.
Conclusions:
iPSC-CMs carrying MYBPC3 PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated nonsense-mediated decay pathway and HCM disease development.
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