Evidence map›Paper›PMID 34802252›Full record

ArticleCirculation. Genomic and precision medicine2021

Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.

Malene E Lindholm, David Jimenez-Morales, Han Zhu, Kinya Seo, David Amar, Chunli Zhao, Archana Raja, Roshni Madhvani, Sarah Abramowitz, Cedric Espenel and 8 more

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

Article in Circulation. Genomic and precision medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
2.2field-weighted citation impact, top 11% 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

19 citing papers in PubMed, 22 citations in OpenAlex.

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  11. A transcriptional enhancer regulates cardiac maturation.Nature cardiovascular research · 2024
    Article
  12. Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.Annals of clinical and translational neurology · 2024
    Article
  13. Review
  14. Article
  15. Review
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  17. Review
  18. Cells · 2022
    Article
  19. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 4 institutions in 2 countries.

Malene E LindholmDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0002-5763-7833
David Jimenez-MoralesDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0003-4356-6461
Han ZhuDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.
Kinya SeoDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0003-0004-7370
David AmarDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.
Chunli ZhaoDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.
Archana RajaDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0001-7079-9872
Roshni MadhvaniDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0002-6876-5419
Sarah AbramowitzDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0001-5515-1752
Cedric EspenelCell Sciences Imaging Facility (C.E.), Stanford University School of Medicine, CA.
Shirley SuttonDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0001-9044-3224
Colleen CaleshuDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.
Gerald J BerryDepartment of Pathology (G.J.B.), Stanford University School of Medicine, CA.ORCID 0000-0002-6176-2629
Kara S MotonagaCenter for Inherited Cardiovascular Diseases (K.S.M., K.D., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0003-4917-1081
Kyla DunnCenter for Inherited Cardiovascular Diseases (K.S.M., K.D., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.
Julia PlattDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0002-2486-9902
Euan A AshleyDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0001-9418-9577
Matthew T WheelerDivision of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.ORCID 0000-0001-8721-3022
Anna Needs Neuroblastoma Answers · USCardiovascular Institute of the South · USStanford University · USGender Studies · CZ

Funding

Stanford MoTrPAC Bioinformatics CenterU24OD026629 · OD · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, WHEELER, MATTHEW THOMAS · 2018 to 2023
$13.9M
Integrative genomics of human heart failureR01HL105993 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI ASHLEY, EUAN A, CAPPOLA, THOMAS P. · 2011 to 2014
$8.9M
Training in Myocardial Biology at Stanford (TIMBS)T32HL094274 · NHLBI · STANFORD UNIVERSITY · PI Euan A Ashley, Daniel Bernstein · 2010 to 2026
$5.0M
Transmission Electron MicroscopeS10RR026780 · NCRR · STANFORD UNIVERSITY · PI TALBOT, WILLIAM S · 2010 to 2010
$412k
OneView 4kX4k sCMOS camera for transmission electron microscopy applicationsS10OD028536 · OD · STANFORD UNIVERSITY · PI MULHOLLAND, JONATHAN W · 2020 to 2020
$195k
ARRA NIH HHSNCRR NIH HHS S10 RR026780NHLBI NIH HHS R01 HL105993NHLBI NIH HHS T32 HL094274NIH HHS S10 OD028536NIH HHS U24 OD026629
6 · The paper itself

Abstract

backgroundACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking

methodsPatients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used co-immunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.

resultsPatient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca

conclusionsTogether, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of

Indexed as

ActininCardiomyopathiesActinsHumansMyocytes, CardiacSarcomeresActininActinsACTN2 protein, humanactinincardiomyopathieshypertrophymass spectrometrymutationsarcomeres

Identifiers

PMID34802252
PMCPMC8692448
OpenAlexW3217610361

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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.