Affinage

TNNI3

Troponin I, cardiac muscle · UniProt P19429

Length
210 aa
Mass
24.0 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNNI3 encodes cardiac troponin I (cTnI), the inhibitory subunit of the cardiac thin-filament troponin complex that governs Ca2+-dependent regulation of contraction and relaxation (PMID:23836688, PMID:32182250). Its inhibitory/switch-peptide region and C-terminus are central regulatory elements: phosphorylation of the cTnI N-terminal extension at Ser23/Ser24 by PKA tunes length-dependent force generation (the Frank-Starling response) by repositioning the cTnI N-terminus relative to cTnC (PMID:23836688, PMID:39328062), while PKC phosphorylation at Ser43/Ser45 slows contraction and relaxation and is functionally interdependent with the PKA sites (PMID:14726296), and PAK3 phosphorylation at Ser151 raises Ca2+-sensitivity by shortening cTnC–cTnI inter-site distances (PMID:20540949). cTnI is additionally arginine-methylated by PRMT1 at R146/R148 within the extended inhibitory peptide; loss of this methylation drives cardiomyocyte hypertrophy, and the HCM mutation at R145 impairs it (PMID:30772011). Beyond the sarcomere, cTnI localizes to the cardiomyocyte nucleus, where it associates with HDAC1 and SMYD1 to influence histone modification and target-gene expression (PMID:30900165), and its own promoter is repressed by HDAC1/HDAC3/HDAC5-mediated histone deacetylation and activated by GATA4/Mef2c binding (PMID:28382690, PMID:27379430, PMID:33378032). Disease-causing mutations cluster in the inhibitory peptide (R145G) and the regulatory C-terminus (R170G/W, D127Y, G203S), altering Ca2+-sensitivity, thin-filament structural integrity, troponin–tropomyosin and troponin–cMyBPC interactions, and beta-adrenergic responsiveness, providing the molecular basis for hypertrophic, restrictive, and dilated cardiomyopathies, with biallelic loss-of-function producing infantile cardiomyopathy and a compensatory fetal TNNI1 isoform switch (PMID:18548271, PMID:32182250, PMID:34502534, PMID:31568572, PMID:36565796).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 Medium

    Defined the genomic structure and transcriptional control region of human TNNI3, establishing that proximal promoter elements drive striated-muscle but not strictly cardiac-specific expression.

    Evidence Genomic cloning, sequencing, and transfection of 5'-flanking constructs in cardiac myocytes, skeletal muscle, and fibroblasts

    PMID:8661099

    Open questions at the time
    • Did not identify the elements conferring cardiac-restricted expression
    • No trans-acting factors mapped to the conserved cis-elements
  2. 2004 High

    Established PKC phosphorylation of cTnI at Ser43/Ser45 as an in vivo brake on contraction/relaxation kinetics that cross-talks with PKA phosphorylation, revealing interdependence among cTnI phospho-sites.

    Evidence Ser43Ala/Ser45Ala transgenic mouse with in situ hemodynamics and back-phosphorylation assay

    PMID:14726296

    Open questions at the time
    • Mechanism of PKC/PKA site cross-talk at the structural level unresolved
    • Phospho-occupancy under physiological signaling not quantified
  3. 2005 Medium

    Showed cTnI is degraded by region-specific N- then C-terminal proteolysis during ischemic arrest, linking C-terminal cleavage to myofibrillar dissociation and identifying adenosine as protective.

    Evidence Region-specific anti-cTnI Western blotting and fractionation in perfused rat hearts under cardioplegia ± adenosine

    PMID:15652960

    Open questions at the time
    • Protease responsible not identified
    • Functional consequence of dissociation not directly measured
  4. 2006 Medium

    Identified a candidate physical partner (DSCR1L2) of cTnI, raising the possibility of regulatory interactions beyond the troponin core.

    Evidence Yeast two-hybrid screen of human heart cDNA with GST pulldown confirmation; exon 2 mapped as binding determinant

    PMID:16516408

    Open questions at the time
    • No functional consequence established
    • Interaction not validated in cardiomyocytes or in vivo
  5. 2010 High

    Defined PAK3-mediated Ser151 phosphorylation as a Ca2+-sensitizing modification that shortens cTnC–cTnI distances, expanding the kinase repertoire tuning thin-filament activation.

    Evidence Steady-state/time-resolved FRET and stopped-flow kinetics on reconstituted thin filaments with cTnI(S151E) phosphomimic

    PMID:20540949

    Open questions at the time
    • In vivo PAK3 phosphorylation of cTnI and its physiological trigger not demonstrated
    • Phosphomimic may not fully replicate genuine phosphorylation
  6. 2013 High

    Established that PKA phosphorylation of cTnI Ser23/Ser24 is a key determinant of length-dependent force generation, mechanistically linking cTnI to the Frank-Starling response.

    Evidence Troponin exchange into permeabilized rat myocytes with PKA treatment and S23D/S24D phosphomimic; length-tension measurements

    PMID:23836688

    Open questions at the time
    • Structural basis for how N-terminal phosphorylation alters length sensing left to later studies
    • Contribution of other myofilament PKA substrates not isolated
  7. 2008 Medium

    Demonstrated that the HCM inhibitory-peptide mutation R145G impairs the beta-adrenergic contractile response, connecting a disease mutation to depressed adrenergic reserve.

    Evidence Adenoviral cTnI-R145G expression in adult rat cardiomyocytes with sarcomere shortening ± isoproterenol

    PMID:18548271

    Open questions at the time
    • Single cell model with overexpression rather than endogenous knock-in
    • Structural mechanism not resolved here
  8. 2014 Medium

    Provided structural and functional mechanism for R145G: it stabilizes Ca2+ coordination in cTnC while blunting N-terminus–inhibitory-peptide coupling and functionally interacts with the cTnT C-terminus to alter thin-filament switching.

    Evidence Molecular dynamics simulations and in vitro motility assays of cTnI-R145G ± cTnT-R278C

    PMID:24418317 PMID:25606687

    Open questions at the time
    • MD predictions of N-terminus repositioning lack direct in vitro/in vivo validation
    • Subunit cross-talk quantified only in reconstituted systems
  9. 2016 Medium

    Revealed dual nuclear/metabolic axes of cTnI biology: HDAC5-mediated promoter deacetylation represses TNNI3 transcription, and an HCM mutation (G203S) impairs Ca2+-channel–mitochondria communication as an early pre-cardiomyopathic event.

    Evidence ChIP of HDAC5 at the cTnI promoter with estrogen/SAHA treatment; patch-clamp and mitochondrial assays in cTnI-G203S transgenic cardiomyocytes

    PMID:27062056 PMID:27379430

    Open questions at the time
    • Direct connection between cTnI mutation and mitochondrial coupling mechanism incompletely defined
    • Promoter regulation studied in neonatal/aging contexts only
  10. 2017 Medium

    Extended epigenetic control of TNNI3 to aging hearts, showing HDAC1/HDAC3 occupancy and GATA4/Mef2c recruitment set cTnI expression and diastolic function.

    Evidence ChIP for HDAC1/HDAC3 and AcH3K9, transcription-factor binding, and echocardiography in aged mice ± EGCG

    PMID:28382690

    Open questions at the time
    • Causal hierarchy among HDACs not dissected
    • EGCG acts pleiotropically beyond the cTnI promoter
  11. 2019 High

    Established three new dimensions of cTnI regulation and pathology: PRMT1 arginine methylation at R146/R148 restraining hypertrophy, nuclear cTnI partnering with HDAC1/SMYD1 to control PDE4d via histone marks, and a fetal TNNI1 isoform switch upon complete TNNI3 loss.

    Evidence Mass spectrometry, in vitro PRMT1 assays and H9c2 hypertrophy readout; nuclear Co-IP and ChIP in cTnI-193His mice; protein/transcript analysis of a homozygous truncating patient biopsy

    PMID:30772011 PMID:30900165 PMID:31568572

    Open questions at the time
    • How methylation loss mechanistically drives hypertrophy not fully defined
    • Nuclear cTnI translocation signals and DNA-targeting specificity unknown
    • Isoform switch documented in a single patient
  12. 2020 High

    Mapped how C-terminal regulatory mutations (R170G/W) destabilize thin filaments and disrupt cTnI/cTnT–cMyBPC-C0C2 interactions, and showed miR-449 controls TNNI3 transcription by sponging HDAC1.

    Evidence Skinned-fiber Ca2+-sensitivity, EM, binding assays and microscale thermophoresis for R170 mutants; luciferase, ChIP and in vivo agomiR for miR-449/HDAC1

    PMID:32182250 PMID:33378032

    Open questions at the time
    • Physiological consequence of disrupted cMyBPC coupling in vivo not measured
    • miR-449 regulation tested mainly in aged hearts
  13. 2021 Medium

    Showed a de novo C-terminal mutation (D127Y) causes infantile restrictive cardiomyopathy through Ca2+-sensitization and thin-filament destabilization, and that troponin-targeting agents can partially restore filament structure.

    Evidence Skinned-fiber force, reconstituted thin-filament structural/binding assays, and levosimendan/EGCg treatment in vitro

    PMID:34502534

    Open questions at the time
    • In vivo or cell-based validation absent
    • Drug effects shown only in vitro
  14. 2024 High

    Used human iPSC-CM and engineered-tissue models with isogenic correction and WT supplementation to show R170W acts as a dominant gain-of-function causing impaired relaxation, and demonstrated a generalizable structural mechanism by which a partner-subunit mutation impairs PKA access to cTnI Ser23/Ser24.

    Evidence CRISPR-corrected and WT-overexpressing R170W iPSC-CM/EHT with mechanical readouts and RNA-seq; FRET/kinetics/MD and hemodynamics defining cTnC–cTnI interface effects on cTnI phosphorylation; AC16 R79C cellular phenotyping

    PMID:38193576 PMID:38497452 PMID:39328062 PMID:39426416

    Open questions at the time
    • Transcriptomic changes (TGF-β, ECM) not mechanistically linked to the contractile defect
    • iPSC-CM maturity limits in vivo extrapolation
  15. 2024 Medium

    Demonstrated a synonymous TNNI3 variant can be pathogenic via cryptic splicing/intron retention, broadening the mutational mechanisms underlying recessive lethal cardiomyopathy.

    Evidence Trio exome sequencing and minigene splicing assay of c.24G>A in compound heterozygosity with a gene deletion

    PMID:36565796

    Open questions at the time
    • Protein-level consequence inferred from splicing, not directly measured
    • Single family
  16. 2025 Medium

    Scaled functional phenotyping to many TNNI3 variants, showing Ca2+-sensitivity predicts pathogenicity while diastolic function correlates with age of onset.

    Evidence High-throughput hiPSC-CM contractile/calcium imaging across variants with clinical correlation (preprint)

    PMID:41446209

    Open questions at the time
    • Preprint, single lab
    • Mechanistic basis of the diastolic-function/onset correlation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How nuclear cTnI is targeted to specific promoters and how its sarcomeric versus nuclear pools are partitioned and coordinated remains unresolved.
  • No nuclear import/retention signal identified for cTnI
  • Genome-wide nuclear cTnI binding sites uncharacterized
  • Interplay between contractile dysfunction and transcriptional reprogramming undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-397014 Muscle contraction 3 R-HSA-4839726 Chromatin organization 3
Partners
HDAC1MYBPC3PRMT1RCAN3SMYD1TNNC1TNNT2TPM1
Complex memberships
cardiac thin filamentcardiac troponin complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The human TNNI3 gene comprises eight exons within 6.2 kb of genomic DNA. A 2300-bp 5'-flanking region drives expression in cardiac myocytes and skeletal muscle cells but not fibroblasts, indicating it is insufficient to confer cardiac-specific expression alone. Several conserved putative cis-acting elements were identified in the proximal promoter. Genomic cloning, sequencing, and transfection assays in cardiac myocytes, skeletal muscle cells, and fibroblasts Genomics Medium 8661099
2004 PKC phosphorylation of cTnI at Ser43 and Ser45 (primarily via PKC-epsilon) slows cardiac contraction and relaxation rates in vivo. Transgenic mice with alanine substitutions at these sites showed ~30% greater +dP/dt and ~18% greater -dP/dt at baseline, with negligible response to isoproterenol or phenylephrine. Mutation of PKC sites was also associated with enhanced PKA-dependent phosphorylation of cTnI, demonstrating interdependence of the phosphorylation sites. Transgenic mouse model with Ser43Ala/Ser45Ala cTnI substitutions; in situ hemodynamics; back-phosphorylation assay American journal of physiology. Heart and circulatory physiology High 14726296
2006 DSCR1L2 (Down syndrome critical region gene 1-like 2) protein physically interacts with human cardiac troponin I (TNNI3). The interaction was identified by yeast two-hybrid screening of a human heart cDNA library and confirmed by yeast co-transformation and GST pulldown. Exon 2 of DSCR1L2 was identified as critical for binding to TNNI3. Yeast two-hybrid (human heart cDNA library), yeast co-transformation, GST fusion protein pulldown assay Gene Medium 16516408
2008 Expression of the HCM-associated cTnI-R145G mutation in adult rat cardiomyocytes significantly decreased baseline sarcomere shortening. Upon beta-adrenergic stimulation with isoproterenol, rates of shortening and relengthening were depressed in cTnI-R145G-expressing cells, indicating that the R145G mutation in the inhibitory peptide region impairs the beta-adrenergic contractile response in a receptor-subtype-dependent manner. Adenovirus-driven expression of cTnI-R145G in adult rat cardiomyocytes; sarcomere shortening measurements with/without beta-adrenergic stimulation Pflugers Archiv : European journal of physiology Medium 18548271
2010 PAK3-mediated phosphorylation of cTnI at Ser151 (studied via S151E phosphomimic) increases Ca2+-sensitivity of cardiac thin filaments by shortening inter-site distances between cTnC and cTnI and reducing kinetic rates of Ca2+ dissociation-induced structural change. The effects mimic those of strong crossbridges on cTnI structural changes. Steady-state and time-resolved FRET; stopped-flow kinetics using reconstituted thin filaments containing cTnI(S151E) Journal of molecular biology High 20540949
2013 Phosphorylation of cTnI at serines 23/24 by PKA is a key regulator of length-dependent force generation (Frank-Starling mechanism) in striated muscle. Exchange of unphosphorylated recombinant cTn into permeabilized rat cardiac myocytes yielded shallow length-tension relationships; PKA treatment or use of cTnI S23D/S24D phosphomimic shifted relationships to steep, recapitulating the length-dependence seen with full PKA treatment. Troponin exchange into permeabilized rat cardiac myocytes and slow-twitch skeletal muscle fibers; length-tension relationship measurements; PKA treatment; S23D/S24D phosphomimic cTnI The Journal of physiology High 23836688
2014 The HCM mutation cTnI-R145G in the inhibitory peptide stabilizes Ca2+-coordinating interactions in cTnC but blunts intrasubunit interactions between the cTnI N-terminal extension (which is phosphorylated at S23/S24 by PKA) and the inhibitory peptide itself. This explains how R145G reduces modulation of troponin function during beta-adrenergic stimulation. Molecular dynamics simulations (triplicate 150 ns) of cTnI-R145G, cTnI-R145G/S23D/S24D, and cTnI-R145G/PS23/PS24 constructs of cTnC(1-161)-cTnI(1-172)-cTnT(236-285) Biophysical journal Low 25606687
2014 The Ca2+-regulatory function of the cTnI inhibitory peptide (Ip) is aided by the C-terminus of cTnT. The HCM mutation cTnI-R145G (in the Ip) and cTnT-R278C together showed that the cTnT mutant rescued some deleterious effects of the cTnI mutant at high Ca2+, but exacerbated loss of thin filament switching-off at low Ca2+, demonstrating functional interaction between these two troponin subunits. In vitro motility assays with reconstituted troponin complexes containing cTnI-R145G and/or cTnT-R278C, varying [Ca2+], temperature, and HMM density Archives of biochemistry and biophysics Medium 24418317
2016 The HCM-associated cTnI-G203S mutation leads to impaired functional communication between the L-type Ca2+ channel (ICa-L) and mitochondria via the cytoskeletal network (involving decreased F-actin-myosin movement and block of the mitochondrial voltage-dependent anion channel), resulting in a 'hypermetabolic' mitochondrial state with greater ICa-L inactivation rate and higher mitochondrial membrane potential. This was observed in pre-cardiomyopathic mice, suggesting it is an early event. Patch clamp electrophysiology; mitochondrial membrane potential measurement; metabolic activity assay; L-type Ca2+ channel antagonist treatment in cTnI-G203S transgenic mouse cardiomyocytes The Journal of physiology Medium 27062056
2017 Low cTnI expression in aging hearts is regulated by histone acetylation. EGCG treatment inhibited HDAC1 and HDAC3 binding at the cTnI promoter, increased AcH3K9 levels at the promoter, and increased binding of transcription factors GATA4 and Mef2c to the cTnI promoter, thereby restoring cTnI expression and improving cardiac diastolic function in aged mice. ChIP assay for HDAC1/HDAC3 binding and AcH3K9 at cTnI promoter; Western blot and RT-PCR for cTnI expression; echocardiography in aged mice treated with EGCG Journal of cellular and molecular medicine Medium 28382690
2019 cTnI is modified by arginine methylation in human myocardium. PRMT1 methylates an extended cTnI inhibitory peptide at R146 and R148 in vitro. Mutations at R145 (associated with HCM) impaired R146/R148 methylation by PRMT1 in vitro. H9c2 cells transfected with methylation-deficient R146A/R148A cTnI showed a 32% increase in cell size (hypertrophy). Reduced cTnI arginine methylation was observed in human hypertrophic cardiomyopathy vs. dilated cardiomyopathy biopsies and in rat cardiac hypertrophy. Western blot for arginine methylation; mass spectrometry identification of methylation sites (R74/R79, R146/R148); in vitro PRMT1 methylation assay with extended inhibitory peptide; H9c2 cell transfection with R146A/R148A cTnI and cell size measurement International journal of cardiology High 30772011
2019 cTnI (both wild-type and RCM-mutant 193His) is present in the nucleus of cardiomyocytes and interacts with histone-modifying enzymes HDAC1 and SMYD1. In RCM mice with the cTnI-193His mutation, PDE4d was downregulated, associated with enhanced acetylation of H3K4 and H3K9 and decreased tri-methylation of H3K4 at the PDE4d promoter. Overexpression of mutated cTnI in cultured cardiomyocytes reduced PDE4d expression. Immunofluorescent labeling and Western blot for nuclear cTnI; co-immunoprecipitation of cTnI with HDAC1 and SMYD1; ChIP assay for histone modifications at PDE4d promoter in cTnI193His transgenic hearts; cardiomyocyte overexpression Science China. Life sciences Medium 30900165
2019 Complete loss of TNNI3 protein (due to homozygous truncating mutation) in pediatric cardiomyopathy is associated with upregulation of the fetal slow skeletal troponin I isoform TNNI1, as confirmed by protein and transcript-level analysis of heart biopsies. This demonstrates a compensatory fetal isoform switch upon TNNI3 loss. Western blot and transcript analysis of heart biopsies from patient with homozygous TNNI3 c.24+2T>A truncating variant Clinical genetics Medium 31568572
2020 cTnI-R170G and R170W mutations (located in the regulatory C-terminus of cTnI) strongly enhanced Ca2+-sensitivity of skinned fibers and increased troponin affinity for tropomyosin (with differential effects on actin binding), destabilized reconstituted thin filament structure (wavy/broken filaments by EM), and disrupted the interaction between troponin and cMyBPC-C0C2. Direct cTnI/cTnT (but not cTnC) binding to cMyBPC-C0C2 was demonstrated by microscale thermophoresis. R170G reduced cTn affinity for cMyBPC-C0C2 and abolished the cMyBPC-C0C2-dependent increase in thin filament activation cooperativity. Skinned fiber Ca2+-sensitivity measurements; electron microscopy of reconstituted thin filaments; cosedimentation/binding assays for troponin-actin/tropomyosin; microscale thermophoresis for troponin-cMyBPC-C0C2 interaction PloS one High 32182250
2020 miR-449 regulates cTnI gene expression by sponging HDAC1. HDAC1-mediated deacetylation of H3K4 and H3K9 at the cTnI promoter reduces cTnI transcription and impairs GATA4 transcription factor binding. miR-449 agomiR treatment in aged mice with low cTnI expression improved cardiac function through this mechanism. Dual-luciferase reporter assay (miR-449/HDAC1 binding); ChIP assay (H3K4, H3K9 acetylation at cTnI promoter; GATA4 binding); in vivo miR-449 agomiR treatment in aged mice with echocardiography European review for medical and pharmacological sciences Medium 33378032
2021 A de novo cTnI-D127Y mutation causes severe infantile restrictive cardiomyopathy. In reconstituted thin filaments, cTnI-D127Y increased Ca2+-sensitivity in skinned fibers, impaired troponin-actin interactions, reduced thin filament structural integrity, and affected inter-subunit troponin interactions. The troponin-targeting agents levosimendan and EGCg partially stabilized thin filament structure and improved contractile function in vitro. Skinned cardiomyocyte/fiber force measurements; reconstituted thin filament binding and structural assays; patient myocardial tissue protein quality control analysis; levosimendan/EGCg treatment in vitro International journal of molecular sciences Medium 34502534
2016 HDAC5 binds to the cTnI promoter and mediates histone deacetylation (reduced H3K9ac) leading to decreased cTnI transcription. Estrogen treatment increased HDAC5 binding at the cTnI promoter in neonatal mouse hearts, while SAHA (HDAC inhibitor) increased H3K9ac and restored cTnI expression. Chromatin immunoprecipitation (ChIP) for HDAC5 at cTnI promoter; HDAC/HAT activity assays; RT-PCR and Western blot for cTnI expression; in vivo estrogen/SAHA treatment Journal of cellular biochemistry Medium 27379430
2005 During cardioplegic arrest, cTnI undergoes site-specific N-terminal proteolysis early and C-terminal proteolysis later, with concomitant dissociation of cTnI from other myofibrillar proteins. Adenosine supplementation of cardioplegic solution significantly attenuated the C-terminal proteolysis and apparent cTnI dissociation from myofibrils, but had no effect on early N-terminal proteolysis. Western blot with region-specific anti-cTnI antibodies on isolated perfused rat hearts subjected to cardioplegic arrest ± adenosine; cellular fractionation The Journal of surgical research Medium 15652960
2022 A TNNI3 synonymous variant (c.24G>A, p.Ala8Ala) causes intron retention (c.24+1_24+45ins) through aberrant cryptic splicing of intron 2, as demonstrated by minigene splicing analysis. Compound heterozygosity with a full gene deletion caused lethal infantile dilated cardiomyopathy. Trio whole-exome sequencing; Sanger sequencing; minigene splicing assay Gene Medium 36565796
2024 The cTnI-R170W mutation (causing RCM) in iPSC-derived cardiomyocytes and engineered heart tissues caused impaired relaxation (prolonged tau, increased relaxation-to-contractile force ratio) that was reversed by CRISPR/Cas9 isogenic correction. Overexpression of wild-type TNNI3 in R170W-iPSC-CMs and EHTs effectively rescued impaired relaxation, demonstrating that the mutation acts dominantly via a gain-of-function mechanism amenable to WT cTnI supplementation. iPSC-derived cardiomyocytes and engineered heart tissue from patient with TNNI3-R170W; CRISPR/Cas9 isogenic correction; wild-type TNNI3 overexpression; calcium kinetics; contractile force measurements Development, growth & differentiation High 38193576
2024 Patient-specific iPSC-derived cardiomyocytes with heterozygous or homozygous TNNI3-R170W exhibited impaired diastolic function (cell motion analysis) without significant changes in intracellular Ca2+ oscillation or troponin I immunocytochemistry or myofibril/mitochondrial ultrastructure. RNA sequencing revealed altered pathways in cardiac muscle development/contraction, ECM-receptor interaction, and TGF-β signaling in RCM-iPSC-CMs. iPSC-derived cardiomyocytes (heterozygous and homozygous TNNI3-R170W vs isogenic correction); cell motion analysis; calcium imaging; immunocytochemistry; electron microscopy; RNA sequencing Journal of the American Heart Association Medium 38497452
2024 The HCM mutation cTnI-R79Cys (TNNI3 c.235C>T) in AC16 human cardiomyocytes upregulates hypertrophy markers ANP, BNP, and MYH7, increases cardiomyocyte size, activates the ERK signaling pathway, impairs mitochondrial function, disrupts cardiomyocyte metabolism, and increases cellular autophagy and apoptosis. Mutant plasmid transfection into AC16 human cardiomyocytes; gene expression analysis; cell size measurement; ERK pathway Western blot; mitochondrial function and metabolic assays; autophagy/apoptosis assays International journal of cardiology Medium 39426416
2024 The R92L-cTnT HCM mutation causes early diastolic dysfunction via allosterically mediated structural changes at the cTnC-cTnI interface that impair PKA accessibility to cTnI (reduced cTnI phosphorylation at S23/S24 region). Time-resolved FRET revealed repositioning of the cTnI N-terminus closer to cTnC with decreased distance distributions flanking the PKA consensus sequence. Constitutive phosphorylation of cTnI (cTnI-D23D24) was sufficient to rescue diastolic function only for R92L-cTnT, not Δ160E-cTnT. 2D echocardiography; Western blot for cTnI phosphorylation; ex vivo hemodynamics; stopped-flow kinetics; time-resolved FRET; molecular dynamics simulations with FRET distance constraints Circulation research High 39328062
2025 High-throughput iPSC-CM measurements of contractile force and calcium cycling distinguished pathogenic from non-pathogenic TNNI3 variants. Clustering by quantitative physiological phenotypes (including diastolic function measures) identified subgroups correlating with age of disease onset in a patient cohort. Increased calcium sensitivity accurately predicted pathogenicity but did not correlate with disease severity, while normalized diastolic function correlated with age of onset (R2=0.6). High-throughput imaging of hiPSC-CMs expressing multiple TNNI3 variants; contractile force measurement; calcium handling analysis; correlation with clinical cohort outcomes bioRxivpreprint Medium 41446209

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circulation. Cardiovascular genetics 199 20215591
2015 TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure-function relationships. Gene 109 26526134
2022 Liposome-Embedded Cu2-AgS Nanoparticle-Mediated Photothermal Immunoassay for Daily Monitoring of cTnI Protein Using a Portable Thermal Imager. Analytical chemistry 99 35533372
1996 Isolation and characterization of the human cardiac troponin I gene (TNNI3). Genomics 73 8661099
1998 The use of cardiac troponin-I (cTnI) to determine the incidence of myocardial ischemia and injury in patients with aneurysmal and presumed aneurysmal subarachnoid hemorrhage. Acta neurochirurgica 71 9522914
1998 Biochemical differences between cTnT and cTnI and their significance for diagnosis of acute coronary syndromes. European heart journal 64 9857935
2017 Clinical Value of Combined Detection of CK-MB, MYO, cTnI and Plasma NT-proBNP in Diagnosis of Acute Myocardial Infarction. Clinical laboratory 63 28271683
2009 [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Revista espanola de cardiologia 59 19150014
2011 A fluoro-microbead guiding chip for simple and quantifiable immunoassay of cardiac troponin I (cTnI). Biosensors & bioelectronics 54 21439810
2011 Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy. Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 53 21533915
2005 Responses of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) to competitive endurance exercise in recreational athletes. International journal of sports medicine 42 16158369
2018 Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Molecular biology reports 41 30362071
2008 Early markers of myocardial injury: cTnI is enough. Clinica chimica acta; international journal of clinical chemistry 41 18992232
2015 Effects of HCM cTnI mutation R145G on troponin structure and modulation by PKA phosphorylation elucidated by molecular dynamics simulations. Biophysical journal 40 25606687
2004 Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo. American journal of physiology. Heart and circulatory physiology 40 14726296
2022 Integrated solar-powered MEMS-based photoelectrochemical immunoassay for point-of-care testing of cTnI protein. Biosensors & bioelectronics 39 36566596
2021 The TDs/aptamer cTnI biosensors based on HCR and Au/Ti3C2-MXene amplification for screening serious patient in COVID-19 pandemic. Biosensors & bioelectronics 39 34256261
2019 Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3. Clinical genetics 37 31568572
2017 Epigallocatechin gallate reverses cTnI-low expression-induced age-related heart diastolic dysfunction through histone acetylation modification. Journal of cellular and molecular medicine 35 28382690
2003 Determination of affinities and antigenic epitopes of bovine cardiac troponin I (cTnI) with monoclonal antibodies by surface plasmon resonance biosensor. Analytical biochemistry 34 12654317
2013 Length dependence of striated muscle force generation is controlled by phosphorylation of cTnI at serines 23/24. The Journal of physiology 33 23836688
2007 Deletion in TNNI3 gene is associated with restrictive cardiomyopathy. International journal of cardiology 33 18006163
2020 SERS-based magnetic immunoassay for simultaneous detection of cTnI and H-FABP using core-shell nanotags. Analytical methods : advancing methods and applications 29 33165490
2014 Ca(2+)-regulatory function of the inhibitory peptide region of cardiac troponin I is aided by the C-terminus of cardiac troponin T: Effects of familial hypertrophic cardiomyopathy mutations cTnI R145G and cTnT R278C, alone and in combination, on filament sliding. Archives of biochemistry and biophysics 29 24418317
2020 An ultrasensitive electrochemical sensing platform for the detection of cTnI based on aptamer recognition and signal amplification assisted by TdT. RSC advances 28 35517933
2014 The novel regulations of MEF2A, CAMKK2, CALM3, and TNNI3 in ventricular hypertrophy induced by arsenic exposure in rats. Toxicology 27 25089838
2014 A fluorogenic heterogeneous immunoassay for cardiac muscle troponin cTnI on a digital microfluidic device. Analytical and bioanalytical chemistry 26 25074544
2022 CRISPR/Cas12a-based electrochemical biosensor for highly sensitive detection of cTnI. Bioelectrochemistry (Amsterdam, Netherlands) 25 35623274
2014 Diagnostic value of analysis of H-FABP, NT-proBNP, and cTnI in heart function in children with congenital heart disease and pneumonia. European review for medical and pharmacological sciences 25 24899611
2020 Aptasensor based on a flower-shaped silver magnetic nanocomposite enables the sensitive and label-free detection of troponin I (cTnI) by SERS. Nanotechnology 24 32927448
2016 The L-type Ca(2+) channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy. The Journal of physiology 22 27062056
2023 Chemiluminescence Biosensor for the Determination of Cardiac Troponin I (cTnI). Biosensors 21 37185530
2013 Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy. Circulation journal : official journal of the Japanese Circulation Society 20 23782526
2020 Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments. PloS one 19 32182250
2012 High prevalence of Arginine to Glutamine substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians. BMC medical genetics 19 22876777
2002 [Proinflammatory cytokines (IL-6, TNF-alpha) and cardiac troponin I (cTnI) in serum of young people with ventricular arrhythmias]. Polskie Archiwum Medycyny Wewnetrznej 19 12412409
2019 Correlations of Changes in Brain Natriuretic Peptide (BNP) and Cardiac Troponin I (cTnI) with Levels of C-Reactive Protein (CRP) and TNF-α in Pediatric Patients with Sepsis. Medical science monitor : international medical journal of experimental and clinical research 17 30956276
2018 Amish nemaline myopathy and dilated cardiomyopathy caused by a homozygous contiguous gene deletion of TNNT1 and TNNI3 in a Mennonite child. European journal of medical genetics 16 30395933
2015 Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy. Cardiovascular journal of Africa 16 25940119
2015 Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population. Molecular genetics and genomics : MGG 16 26169204
2010 Ventricular septal defect and restrictive cardiomyopathy in a paediatric TNNI3 mutation carrier. Cardiology in the young 15 20569525
2006 Proteins encoded by human Down syndrome critical region gene 1-like 2 (DSCR1L2) mRNA and by a novel DSCR1L2 mRNA isoform interact with cardiac troponin I (TNNI3). Gene 15 16516408
2001 Evaluation of Stratus CS stat fluorimetric analyser for measurement of cardiac markers Troponin I (cTnI), creatine kinase MB (CK-MB), and myoglobin. Journal of clinical laboratory analysis 15 11793431
2019 Epigenetic regulation of phosphodiesterase 4d in restrictive cardiomyopathy mice with cTnI mutations. Science China. Life sciences 14 30900165
2015 Clinical assessment and C-reactive protein (CRP), haptoglobin (Hp), and cardiac troponin I (cTnI) values of brachycephalic dogs with upper airway obstruction before and after surgery. Canadian journal of veterinary research = Revue canadienne de recherche veterinaire 14 25673910
2004 Role of heart-type fatty acid binding protein in early detection of acute myocardial infarction in comparison with cTnI, CK-MB and myoglobin. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 14 15641689
2019 The inhibitory subunit of cardiac troponin (cTnI) is modified by arginine methylation in the human heart. International journal of cardiology 13 30772011
2002 Improved identification of acute coronary syndromes with second generation cardiac troponin I assay: utility of 2-hour delta cTnI > or = +0.02 ng/mL. The Journal of emergency medicine 12 11858918
2023 Expression and Clinical Significance of Serum sST2, BDNF, CTnI, and BUN/Cr in Patients With Heart Failure. Alternative therapies in health and medicine 11 36074967
2023 Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature. Genes 11 36981019
2021 De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents. International journal of molecular sciences 11 34502534
2019 A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3). BMC medical genetics 11 30953456
2016 Transitioning high sensitivity cardiac troponin I (hs-cTnI) into routine diagnostic use: More than just a sensitivity issue. Practical laboratory medicine 11 28856194
2017 Kolaviron attenuated arsenic acid induced-cardiorenal dysfunction via regulation of ROS, C-reactive proteins (CRP), cardiac troponin I (CTnI) and BCL2. Journal of traditional and complementary medicine 10 29992111
2001 Postoperative patterns and kinetics of cTnI, cTnT, CK-MB-activity and CK-activity after elective aortic valve replacement. Swiss medical weekly 10 11759175
2022 Positive Relationship of RDW with NT-proBNP and cTnI in Acute Myocardial Infarction Patients. Clinical laboratory 9 35704727
2022 Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants. Molecular diagnosis & therapy 9 35838873
2017 Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation. Korean circulation journal 9 28382084
2010 Structural and kinetic effects of PAK3 phosphorylation mimic of cTnI(S151E) on the cTnC-cTnI interaction in the cardiac thin filament. Journal of molecular biology 9 20540949
2022 CTnI diagnosis in myocardial infarction using G-quadruplex selective Ir(Ⅲ) complex as effective electrochemiluminescence probe. Talanta 8 35687951
2020 MiR-449 improves cardiac function by regulating HDAC1 and cTnI. European review for medical and pharmacological sciences 8 33378032
2015 A Double Heterozygous Mutation of TNNI3 Causes Hypertrophic Cardiomyopathy in a Han Chinese Family. Cardiology 8 26506446
2014 Role of serum myeloperoxidase, CPK, CK-MB, and cTnI tests in early diagnosis of myocardial ischemia during ERCP. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 8 25141318
2024 Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy. Development, growth & differentiation 7 38193576
2021 The Diagnostic Value of Plasma miRNA-497, cTnI, FABP3 and GPBB in Pediatric Sepsis Complicated with Myocardial Injury. Therapeutics and clinical risk management 7 34113113
2018 The TNNI3 Arg192His mutation in a 13-year-old girl with left ventricular noncompaction. Journal of cardiology cases 7 30279906
2016 The diagnostic value of two commercially available human cTnI assays in goat kids with myocarditis. Veterinary clinical pathology 7 26802431
2008 Expression of cTnI-R145G affects shortening properties of adult rat cardiomyocytes. Pflugers Archiv : European journal of physiology 7 18548271
2023 High-sensitive cardiac troponin I (hs-cTnI) concentrations in newborns diagnosed with spinal muscular atrophy. Frontiers in pediatrics 6 38034835
2021 TNNI3 and KCNQ1 co-inherited variants in a family with hypertrophic cardiomyopathy and long QT phenotypes: A case report. Molecular genetics and metabolism reports 6 33777698
2013 Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene. Journal of biomedical research 6 24474965
2022 Diagnostic Value of Echocardiography Combined with Serum h-FABP and cTnI in Myocardial Infarction and Its Evaluation Value in Left Ventricular Function. Evidence-based complementary and alternative medicine : eCAM 5 35656464
2020 cTnI, BNP and CRP profiling after seizures in patients with drug-resistant epilepsy. Seizure 5 32563168
2024 Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy. Journal of the American Heart Association 4 38497452
2024 Ckip-1 3'UTR alleviates prolonged sleep deprivation induced cardiac dysfunction by activating CaMKK2/AMPK/cTNI pathway. Molecular biomedicine 4 38871861
2018 Correlations of inhaled NO with the cTnI levels and the plasma clotting factor in rabbits with acute massive pulmonary embolism. Acta cirurgica brasileira 4 30208128
2016 Suberoylanilide Hydroxamic Acid Restores Estrogen Reduced-cTnI Expression in Neonatal Hearts of Mice. Journal of cellular biochemistry 4 27379430
2012 Effects of the glucose-lowering rate on cTnI and hs-CRP serum levels in type 2 diabetics. Human immunology 4 23220502
2025 A New Chemiluminescence-Based Rapid Diagnostic Testing Platform with Sequential Dual-Flow Strips for Cardiac Troponin I (cTnI). Analytical chemistry 3 40152334
2024 Increased cTnI Predicts Early Death in Patients with Severe Fever with Thrombocytopenia: A Multicenter Study in North China. Infection and drug resistance 3 38919833
2024 Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy. Molecular genetics & genomic medicine 3 38924380
2021 [Identification of variants in TNNI3 gene in two children with restrictive cardiomyopathy]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 34365612
2021 Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying TNNI3 mutations. Stem cell research 3 34798544
2025 Exploring the c.406 C > T variant in TNNI3 gene: pathogenic insights into restrictive cardiomyopathy. BMC medical genomics 2 40307908
2024 Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant. International journal of cardiology 2 39426416
2023 A carbon quantum layer modified BiVO4 photoelectrochemical aptamer biosensor for ultra-sensitive cTnI biomarker detection based on the interface nephelauxetic effect and heterojunction assistance. Journal of materials chemistry. B 2 37782550
2022 Identification of a novel TNNI3 synonymous variant causing intron retention in autosomal recessive dilated cardiomyopathy. Gene 2 36565796
2018 A Novel TNNI3 Gene Mutation (c.235C>T/ p.Arg79Cys) Found in a Thirty-eight-year-old Women with Hypertrophic Cardiomyopathy. Open life sciences 2 33817105
2016 Potential use of pericardial cTnI, Mg2+ and Ca2+ in the forensic investigation of seawater drowning in Greece: An initial assessment. Legal medicine (Tokyo, Japan) 2 27890099
2012 Temperature-dependent instability of the cTnI subunit in NIST SRM2921 characterized by tryptic peptide mapping. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2 22771105
2005 Adenosine attenuates C-terminal but not N-terminal proteolysis of cTnI during cardioplegic arrest. The Journal of surgical research 2 15652960
2025 Serum exosomal lncRNA LINC00472 combined with serum CK-MB and cTnI as diagnostic biomarker for acute myocardial infarction. Heart & lung : the journal of critical care 1 40609177
2025 Multiparametric Assessment of TNNI3 Variant Phenotypes in Human iPSC-Cardiomyocytes Correlates with Disease Severity in Patients. bioRxiv : the preprint server for biology 1 41446209
2024 Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant. Human genome variation 1 38548731
2024 Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation. Circulation research 1 39328062
2024 Bioinformatics design of peptide binding to the human cardiac troponin I (cTnI) in biosensor development for myocardial infarction diagnosis. PloS one 1 39436888
2024 Machine Learning Diagnostic Model for Early Stage NSTEMI: Using hs-cTnI 1/2h Changes and Multiple Cardiovascular Biomarkers. Diagnostics (Basel, Switzerland) 1 39451645
2024 Case Report: Restrictive cardiomyopathy due to a rare mutation in troponin I gene (TNNI3) in a patient. Frontiers in cardiovascular medicine 1 39635265
2020 Chondroid and Osseous Metaplasia of the Central Fibrous Body in Adolescent Hearts with Mutations in TNNI3 and TNNT2 genes. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1 32758068
2002 [Coronary flow velocity reserve and collateral resistance after recanalization of chronic total coronary occlusions and periprocedural CK and cTNI elevation]. Zeitschrift fur Kardiologie 1 12442197

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