Evidence map›Paper›PMID 26498512›Full record

ArticleBMC medical genetics2015

Establishing disease causality for a novel gene variant in familial dilated cardiomyopathy using a functional in-vitro assay of regulated thin filaments and human cardiac myosin.

Stephen Pan, Ruth F Sommese, Karim I Sallam, Suman Nag, Shirley Sutton, Susan M Miller, James A Spudich, Kathleen M Ruppel, Euan A Ashley

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

Article in BMC medical genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.2field-weighted citation impact, top 42% 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

4 citing papers in PubMed, 5 citations in OpenAlex.

  1. Review
  2. Review
  3. Variant R94C inJournal of the American Heart Association · 2020
    Article
  4. 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

9 authors at 4 institutions in 1 country.

Stephen PanLeon H. Charney Division of Cardiology, NYU Langone Medical Center, New York, NY, USA. Stephen.Pan@nyumc.org.
Ruth F SommeseDepartment of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA. rsommese@umn.edu.
Karim I SallamDepartments of Medicine (Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA. sallam@stanford.edu.
Suman NagDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. sumannag@stanford.edu.
Shirley SuttonDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. scsutton@stanford.edu.
Susan M MillerDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. Susan.MillerPhD@ucsf.edu.
James A SpudichDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. jspudich@stanford.edu.
Kathleen M RuppelDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. kruppel@stanford.edu.
Euan A AshleyDepartments of Medicine (Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA. euan@stanford.edu.
Stanford University · USNYU Langone Health · USUniversity of California, San Francisco · USUniversity of Minnesota · US

Funding

MYOSIN MOVEMENT IN VITRO: MOLECULAR CHARACTERIZATIONR01GM033289 · NIGMS · STANFORD UNIVERSITY · PI SPUDICH, JAMES · 1985 to 2024
$13.6M
Training in Myocardial Biology at Stanford (TIMBS)T32HL094274 · NHLBI · STANFORD UNIVERSITY · PI Euan A Ashley, Daniel Bernstein · 2010 to 2026
$5.0M
NHLBI NIH HHS T32 HL094274NIGMS NIH HHS GM33289NIGMS NIH HHS R01 GM033289
6 · The paper itself

Abstract

backgroundAs next generation sequencing for the genetic diagnosis of cardiovascular disorders becomes more widely used, establishing causality for putative disease causing variants becomes increasingly relevant. Diseases of the cardiac sarcomere provide a particular challenge in this regard because of the complexity of assaying the effect of genetic variants in human cardiac contractile proteins.

resultsIn this study we identified a novel variant R205Q in the cardiac troponin T gene (TNNT2). Carriers of the variant allele exhibited increased chamber volumes associated with decreased left ventricular ejection fraction. To clarify the causal role of this variant, we generated recombinant variant human protein and examined its calcium kinetics as well as the maximally activated ADP release of human β-cardiac myosin with regulated thin filaments containing the mutant troponin T. We found that the R205Q mutation significantly decreased the calcium sensitivity of the thin filament by altering the effective calcium dissociation kinetics.

conclusionsThe development of moderate throughput post-genomic assays is an essential step in the realization of the potential of next generation sequencing. Although technically challenging, biochemical and functional assays of human cardiac contractile proteins of the thin filament can be achieved and provide an orthogonal source of information to inform the question of causality for individual variants.

Indexed as

MutationAdultCalciumCardiac MyosinsCardiomyopathy, DilatedChildChild, PreschoolFemaleGenetic Predisposition to DiseaseHumansIn Vitro TechniquesMaleMyosin Heavy ChainsRecombinant ProteinsStroke VolumeTroponin TCalciumCardiac MyosinsMYH7 protein, humanMyosin Heavy ChainsRecombinant ProteinsTNNT2 protein, humanTroponin T

Identifiers

PMID26498512
PMCPMC4620603
OpenAlexW1844965663

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.