Evidence map›Paper›PMID 25031304›Full record

ArticleCirculation. Cardiovascular genetics2014

Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy.

Adam S Helms, Frank M Davis, David Coleman, Sarah N Bartolone, Amelia A Glazier, Francis Pagani, Jaime M Yob, Sakthivel Sadayappan, Ellen Pedersen, Robert Lyons and 4 more

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

Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.

0numbers the graph read from it
0cells of the map it votes in
68citing papers in PubMed
4.5field-weighted citation impact, top 4% 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

68 citing papers in PubMed, 100 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Article
  5. Review
  6. Article
  7. Obstructive hypertrophic cardiomyopathy: from genetic insights to a multimodal therapeutic approach with mavacamten, aficamten, and beyond.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2024
    Review
  8. Review
  9. Article
  10. Article
  11. Multiplexed Functional Assessments ofCirculation. Genomic and precision medicine · 2024
    Article
  12. Article
  13. Myosin-binding protein H-like regulates myosin-binding protein distribution and function in atrial cardiomyocytes.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  14. Article
  15. Review
  16. Article
  17. An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2023
    Review
  18. Review
  19. Article
  20. Article

8 more citing papers are in PubMed but not listed here.

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

14 authors at 1 institution in 1 country.

Adam S HelmsFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Frank M DavisFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
David ColemanFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Sarah N BartoloneFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Amelia A GlazierFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Francis PaganiFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Jaime M YobFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Sakthivel SadayappanFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Ellen PedersenFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Robert LyonsFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Margaret V WestfallFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Richard JonesFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Mark W RussellFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
Sharlene M DayFrom the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.). sday@umich.edu.
Loyola University Chicago · US

Funding

TRAINING IN MOLECULAR AND CELLULAR CARDIOLOGYT32HL007853 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI David J. Pinsky · 1996 to 2026
$11.6M
SYTEMS AND INTEGRATIVE BIOLOGYT32GM008322 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LOW, MALCOLM JAMES · 1990 to 2020
$5.7M
Fast myosin binding protein-C and cardiac contractility in heart failureR01HL105826 · NHLBI · UNIVERSITY OF CINCINNATI · PI SADAYAPPAN, SAKTHIVEL · 2011 to 2025
$4.5M
Regulation of Proteasome Function in CardiomyopathiesR01HL093338 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI DAY, SHARLENE M · 2009 to 2013
$1.9M
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarctiK02HL114749 · NHLBI · UNIVERSITY OF CINCINNATI · PI SADAYAPPAN, SAKTHIVEL · 2012 to 2016
$498k
NHLBI NIH HHS K02 HL114749NHLBI NIH HHS K02HL114749NHLBI NIH HHS R01 HL093338NHLBI NIH HHS R01HL093338NHLBI NIH HHS R01 HL105826NHLBI NIH HHS R01HL105826NHLBI NIH HHS T32 HL007853NIGMS NIH HHS T32 GM008322
6 · The paper itself

Abstract

backgroundHeterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM. METHODS AND

resultsSarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in MYBPC3, the average ratio of mutant:wild-type transcripts was ≈1:5, in contrast to ≈1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total MYBPC3 mRNA was significantly increased by 9-fold in HCM samples with MYBPC3 mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between MYBPC3 mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%.

conclusionsThese results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by MYBPC3 truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild-type proteins. These mutation-specific properties may distinctly influence disease phenotypes.

Indexed as

AllelesCardiomyopathy, HypertrophicCarrier ProteinsEchocardiographyFemaleGene Expression RegulationGenotypeHeterozygoteHumansMaleMiddle AgedMutation, MissenseMyocardiumMyosin Binding Protein CProteomicsRNA, MessengerCarrier ProteinsMyosin Binding Protein CRNA, Messengercardiomyopathy, hypertrophicgene expressiongene expression regulationhumansproteomicssarcomeres

Identifiers

PMID25031304
PMCPMC4254656
OpenAlexW2332903153

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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.