Evidence map›Paper›PMID 30586709›Full record

ArticleCirculation2019

A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay.

Timon Seeger, Rajani Shrestha, Chi Keung Lam, Caressa Chen, Wesley L McKeithan, Edward Lau, Alexa Wnorowski, George McMullen, Matthew Greenhaw, Jaecheol Lee and 9 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.

0numbers the graph read from it
0cells of the map it votes in
92citing papers in PubMed
12.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

92 citing papers in PubMed, 122 citations in OpenAlex.

  1. Article
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  8. Hypertrophic Cardiomyopathy is a Disease of Sarcomere Proteins.Methodist DeBakey cardiovascular journal · 2026
    Review
  9. Advances in human induced pluripotent stem cell (hiPSC)-based disease modelling in cardiogenetics.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025
    Article
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32 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors at 3 institutions in 2 countries.

Timon SeegerStanford 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.
Rajani ShresthaStanford 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.
Chi Keung LamStanford 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.
Caressa ChenStanford 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.
Wesley L McKeithanStanford 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.
Edward LauStanford 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.
Alexa WnorowskiStanford 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.
George McMullenDepartment of Cardiothoracic Surgery (G.M., M.G., I.K.), Stanford University School of Medicine, CA.
Matthew GreenhawStanford 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.
Jaecheol LeeStanford 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.
Angelos OikonomopoulosStanford 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.
Soah LeeStanford 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.
Huaxiao YangStanford 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.
Mark MercolaStanford 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.
Matthew WheelerStanford 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.
Euan A AshleyStanford 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.
Fan YangDepartment of Bioengineering (A.W., S.L., F.Y.), Stanford University School of Medicine, CA.
Ioannis KarakikesStanford 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.
Joseph C WuStanford 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.
MACOM (United States) · USCardiovascular Institute of the South · USStanford University · US

Funding

Elucidating Mechanism of Cardiac Fibrosis with Cell Village of Pooled Human iPSCsR01HL130020 · NHLBI · STANFORD UNIVERSITY · PI Ronglih Liao, MARK MERCOLA · 2016 to 2026
$7.3M
VECTOR COREP30NS069375 · NINDS · STANFORD UNIVERSITY · PI STEINBERG, GARY K · 2011 to 2019
$6.3M
Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCsR01HL141851 · NHLBI · STANFORD UNIVERSITY · PI WONG, WING H., WU, JOSEPH C. · 2018 to 2025
$5.7M
Genome Editing of Human iPSCs to Study Inherited Hypertrophic CardiomyopathyR01HL126527 · NHLBI · STANFORD UNIVERSITY · PI QI, LEI STANLEY, WU, JOSEPH C. · 2015 to 2022
$5.4M
Training in Myocardial Biology at Stanford (TIMBS)T32HL094274 · NHLBI · STANFORD UNIVERSITY · PI Euan A Ashley, Daniel Bernstein · 2010 to 2026
$5.0M
Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicineR01HL139679 · NHLBI · STANFORD UNIVERSITY · PI Ioannis Karakikes · 2018 to 2026
$4.2M
A Systems Biology Approach to Study Cardiac Arrhythmias: iPS Cells and In Silico ModelingR01HL128170 · NHLBI · STANFORD UNIVERSITY · PI ALTMAN, RUSS BIAGIO, CLANCY, COLLEEN E · 2015 to 2018
$3.0M
miR-152: A Novel Regulator of Diabetic CardiomyopathyR00HL104002 · NHLBI · STANFORD UNIVERSITY · PI KARAKIKES, IOANNIS · 2017 to 2019
$893k
NHLBI NIH HHS R00 HL104002NHLBI NIH HHS R01 HL126527NHLBI NIH HHS R01 HL128170NHLBI NIH HHS R01 HL130020NHLBI NIH HHS R01 HL139679NHLBI NIH HHS R01 HL141851NINDS NIH HHS P30 NS069375
6 · The paper itself

Abstract

backgroundHypertrophic 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).

methodsIsogenic 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.

resultsWe 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.

conclusionsiPSC-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.

Indexed as

Calcium SignalingCardiomyopathy, HypertrophicCarrier ProteinsCell DifferentiationCell LineCodon, NonsenseDisease ProgressionGene EditingGene Expression ProfilingHaploinsufficiencyHumansMutationMyocytes, CardiacMyosin Binding Protein CPluripotent Stem CellsRNA, MessengerCarrier ProteinsCodon, NonsenseMyosin Binding Protein CRNA, Messengercardiomyocyteshypertrophic cardiomyopathy

Identifiers

PMID30586709
PMCPMC6443405
OpenAlexW2895168260

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.