Details for: TNNI3

Gene ID: 7137

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TNNI3

Ensembl ID: ENSG00000129991

Description: troponin I3, cardiac type

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • cardiac muscle cell CL0000746
    CSI 35.08
    rCSI 50.34%
    PRS 92.28
  • epithelial cell CL0000066
    CSI 21.66
    rCSI 33.29%
    PRS 88.73
  • ependymal cell CL0000065
    CSI 21.52
    rCSI 43.67%
    PRS 86.03
  • fallopian tube secretory epithelial cell CL4030006
    CSI 19.92
    rCSI 19.18%
    PRS 95.92
  • ciliated cell CL0000064
    CSI 16.57
    rCSI 26.84%
    PRS 92.65
  • ventricular cardiac muscle cell CL2000046
    CSI 16.34
    rCSI 55.99%
    PRS 96.65
  • mural cell CL0008034
    CSI 12.54
    rCSI 42.48%
    PRS 94.65
  • enteroendocrine cell CL0000164
    CSI 10.48
    rCSI 14.33%
    PRS 95
  • capillary endothelial cell CL0002144
    CSI 10.23
    rCSI 18.75%
    PRS 94.77
  • cardiac neuron CL0010022
    CSI 9.43
    rCSI 30.16%
    PRS 96.18
  • smooth muscle cell CL0000192
    CSI 9.04
    rCSI 21.55%
    PRS 94.2
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 7.78
    rCSI 17.73%
    PRS 92.13
  • cardiac endothelial cell CL0010008
    CSI 7.63
    rCSI 30.8%
    PRS 97.08
  • vascular associated smooth muscle cell CL0000359
    CSI 7.61
    rCSI 24.69%
    PRS 96.49
  • cardiac blood vessel endothelial cell CL0010006
    CSI 7.47
    rCSI 52.83%
    PRS 92.89
  • fibroblast of cardiac tissue CL0002548
    CSI 6.95
    rCSI 33.3%
    PRS 97.37
  • macrophage CL0000235
    CSI 6.88
    rCSI 12.52%
    PRS 96.05
  • pericyte CL0000669
    CSI 6.47
    rCSI 17.23%
    PRS 79.48
  • fibroblast CL0000057
    CSI 6.33
    rCSI 18.2%
    PRS 89.97
  • multi-ciliated epithelial cell CL0005012
    CSI 6.32
    rCSI 6.31%
    PRS 93.63
  • Schwann cell CL0002573
    CSI 6.17
    rCSI 17.54%
    PRS 94.81
  • epicardial adipocyte CL1000309
    CSI 6.09
    rCSI 19.82%
    PRS 95.01
  • glial cell CL0000125
    CSI 6.07
    rCSI 23.12%
    PRS 93.14
  • endocardial cell CL0002350
    CSI 5.31
    rCSI 25.43%
    PRS 95
  • megakaryocyte CL0000556
    CSI 4.82
    rCSI 20.9%
    PRS 96.22
  • regular atrial cardiac myocyte CL0002129
    CSI 4.27
    rCSI 13.73%
    PRS 94.29
  • regular ventricular cardiac myocyte CL0002131
    CSI 3.37
    rCSI 21.04%
    PRS 93.01
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 2.59
    rCSI 3.39%
    PRS 99.05
  • adipocyte CL0000136
    CSI 2.33
    rCSI 3%
    PRS 92.42
  • mesothelial cell CL0000077
    CSI 2.02
    rCSI 7.91%
    PRS 88.74

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [TNNI3](/details-gene/7137), or Troponin I3, cardiac type, is a protein-coding gene located on chromosome 19q13.42. It encodes the cardiac-specific isoform of troponin I, a critical component of the troponin complex in the thin filaments of the sarcomere. Functionally, [TNNI3](/details-gene/7137) acts as a calcium-sensitive molecular switch, inhibiting the ATPase activity of the actomyosin head and thereby preventing muscle contraction in the absence of calcium. Its expression is overwhelmingly specific to cardiac tissue, making it a definitive biomarker for [cardiac muscle cell](/details-cell/CL0000746) identity and injury. Mutations in this gene are clinically associated with inherited cardiomyopathies, including familial hypertrophic cardiomyopathy ([115210](https://omim.org/entry/115210)) and restrictive cardiomyopathy ([191044](https://omim.org/entry/191044)). ## Cellular Roles and Expression Landscape The expression profile of [TNNI3](/details-gene/7137) underscores its highly specialized role in cardiac physiology. **Overall**, the gene exhibits its highest significance in [cardiac muscle cell](/details-cell/CL0000746) (CSI: 35.08) and more specifically, [ventricular cardiac muscle cell](/details-cell/CL2000046) (CSI: 16.34). This dominant expression is consistent with its canonical function as a core regulatory protein within the cardiac sarcomere. The high significance scores in related cardiovascular cell types, including [cardiac neuron](/details-cell/CL0010022), [smooth muscle cell](/details-cell/CL0000192), and various endothelial cells such as [capillary endothelial cell](/details-cell/CL0002144) and [cardiac endothelial cell](/details-cell/CL0010008), further establish its central role within the heart's cellular ecosystem. Interestingly, the data also indicate significant expression in several non-cardiac cell types, including [epithelial cell](/details-cell/CL0000066), [ependymal cell](/details-cell/CL0000065), and [fallopian tube secretory epithelial cell](/details-cell/CL4030006). While this may reflect shared regulatory programs or potential non-canonical functions related to calcium-dependent cytoskeletal regulation, the primary identity of [TNNI3](/details-gene/7137) remains that of a specific and essential workhorse for cardiac muscle function. ## Pathways and Molecular Function The functional annotations for [TNNI3](/details-gene/7137) are tightly aligned with its role in the heart. It is a key participant in biological processes such as [Cardiac muscle contraction (GO:0060048)](https://www.ebi.ac.uk/QuickGO/term/GO:0060048) and the overarching [Muscle contraction (R-HSA-397014)](https://reactome.org/content/detail/R-HSA-397014) pathway. Its molecular function is defined by its ability to bind to other key proteins in the sarcomere, including [Actin binding (GO:0003779)](https://www.ebi.ac.uk/QuickGO/term/GO:0003779), [Troponin c binding (GO:0030172)](https://www.ebi.ac.uk/QuickGO/term/GO:0030172), and [Troponin t binding (GO:0031014)](https://www.ebi.ac.uk/QuickGO/term/GO:0031014). Structurally, [TNNI3](/details-gene/7137) is an integral component of the [Cardiac troponin complex (GO:1990584)](https://www.ebi.ac.uk/QuickGO/term/GO:1990584) located at the [Sarcomere (GO:0030017)](https://www.ebi.ac.uk/QuickGO/term/GO:0030017). The function of [TNNI3](/details-gene/7137) is dynamically modulated by post-translational modifications, particularly phosphorylation by kinases such as PKA, PAK, and PKD, which alter the myofilament's sensitivity to calcium and regulate contractile force ([Link](https://doi.org/10.1111/j.1432-1033.1997.00329.x), [Link](https://doi.org/10.1161/01.res.0000035246.27856.53), [Link](https://doi.org/10.1161/01.res.0000149299.34793.3c)). Dysregulation of these phosphorylation events has been implicated in heart failure ([Link](https://doi.org/10.1161/circulationaha.112.096388)). ## Research Directions Given its established role in both normal cardiac function and inherited cardiomyopathies, research on [TNNI3](/details-gene/7137) is critical for understanding heart disease. The link between specific mutations and clinical phenotypes provides a direct path for investigating disease mechanisms. Based on the available data, several testable hypotheses can be proposed: 1. Disease-causing mutations in [TNNI3](/details-gene/7137), such as those associated with hypertrophic cardiomyopathy, alter the protein's conformation and phosphorylation status, leading to aberrant calcium sensitivity of the myofilament and contributing to the development of cardiac hypertrophy and diastolic dysfunction. 2. The observed expression of [TNNI3](/details-gene/7137) in non-muscle cell types, such as [ependymal cell](/details-cell/CL0000065) and specific secretory epithelial cells, may serve a non-canonical function in modulating actin cytoskeleton dynamics or calcium signaling that is distinct from its role in sarcomeric contraction. To address the first hypothesis, a key experiment could be designed: * **Experimental Approach:** Generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying patient-specific [TNNI3](/details-gene/7137) mutations using CRISPR-Cas9 genome editing. These engineered cells, alongside isogenic controls, can be matured into cardiac microtissues. A combination of phosphoproteomics (mass spectrometry) and functional assays (calcium transient imaging, contractility force measurement) would be used to directly assess how specific mutations alter [TNNI3](/details-gene/7137) phosphorylation and impact cellular function. **Therapeutic Potential:** [TNNI3](/details-gene/7137) itself is a challenging therapeutic target for direct inhibition or activation, as crude modulation would likely have severe consequences on cardiac contractility. However, its central role makes it an important node for intervention. For inherited cardiomyopathies caused by [TNNI3](/details-gene/7137) mutations, gene therapy approaches aimed at correcting the faulty gene represent a potential long-term strategy. More immediately, targeting the upstream kinases and phosphatases that regulate [TNNI3](/details-gene/7137) phosphorylation offers a more druggable approach to normalize myofilament function in the context of heart failure.

Genular Protein ID: 2290306481

Symbol: TNNI3_HUMAN

Name: Troponin I, cardiac muscle

UniProtKB Accession Codes:

P19429

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CPTC 1 CTD 1 ChEMBL 1 ChiTaRS 1 ComplexPortal 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 1 EMBL 3 EMDB 2 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 24 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 9 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 39 PDBsum 39 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 2226790

Title: Molecular cloning of human cardiac troponin I using polymerase chain reaction.

PubMed ID: 2226790

DOI: 10.1016/0014-5793(90)81234-f

PubMed ID: 8406024

Title: Cloning and expression in Escherichia coli of the cDNA encoding human cardiac troponin I.

PubMed ID: 8406024

DOI: 10.1016/0378-1119(93)90308-p

PubMed ID: 1934363

Title: Troponin I isoform expression in human heart.

PubMed ID: 1934363

DOI: 10.1161/01.res.69.5.1409

PubMed ID: 8661099

Title: Isolation and characterization of the human cardiac troponin I gene (TNNI3).

PubMed ID: 8661099

DOI: 10.1006/geno.1996.0317

PubMed ID: 2226863

Title: A common motif of two adjacent phosphoserines in bovine, rabbit and human cardiac troponin I.

PubMed ID: 2226863

DOI: 10.1016/0014-5793(90)81046-q

PubMed ID: 9346285

Title: The ordered phosphorylation of cardiac troponin I by the cAMP-dependent protein kinase -- structural consequences and functional implications.

PubMed ID: 9346285

DOI: 10.1111/j.1432-1033.1997.00329.x

PubMed ID: 12242269

Title: p21-activated kinase increases the calcium sensitivity of rat triton-skinned cardiac muscle fiber bundles via a mechanism potentially involving novel phosphorylation of troponin I.

PubMed ID: 12242269

DOI: 10.1161/01.res.0000035246.27856.53

PubMed ID: 15514163

Title: Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function.

PubMed ID: 15514163

DOI: 10.1161/01.res.0000149299.34793.3c

PubMed ID: 15601779

Title: Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I.

PubMed ID: 15601779

DOI: 10.1073/pnas.0404341102

PubMed ID: 18986304

Title: Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase 1.

PubMed ID: 18986304

DOI: 10.1042/bj20081340

PubMed ID: 22972900

Title: Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart.

PubMed ID: 22972900

DOI: 10.1161/circulationaha.112.096388

PubMed ID: 10387074

Title: Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C.

PubMed ID: 10387074

DOI: 10.1021/bi9901679

PubMed ID: 12060657

Title: Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil.

PubMed ID: 12060657

DOI: 10.1074/jbc.m203896200

PubMed ID: 9241277

Title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.

PubMed ID: 9241277

DOI: 10.1038/ng0897-379

PubMed ID: 11815426

Title: Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.

PubMed ID: 11815426

DOI: 10.1161/hc0402.102990

PubMed ID: 12531876

Title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.

PubMed ID: 12531876

DOI: 10.1172/jci16336

PubMed ID: 12707239

Title: Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

PubMed ID: 12707239

DOI: 10.1161/01.cir.0000066323.15244.54

PubMed ID: 12974739

Title: Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.

PubMed ID: 12974739

DOI: 10.1034/j.1399-0004.2003.00151.x

PubMed ID: 15070570

Title: Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy.

PubMed ID: 15070570

DOI: 10.1016/s0140-6736(04)15468-8

PubMed ID: 16199542

Title: Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.

PubMed ID: 16199542

DOI: 10.1136/jmg.2005.033886

PubMed ID: 19590045

Title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.

PubMed ID: 19590045

DOI: 10.1161/circresaha.109.196055

PubMed ID: 21846512

Title: Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy.

PubMed ID: 21846512

DOI: 10.1016/j.ejmg.2011.07.005

Sequence Information:

  • Length: 210
  • Mass: 24008
  • Checksum: 20A804F8C24AE1B0
  • Sequence:
    • MADGSSDAAR EPRPAPAPIR RRSSNYRAYA TEPHAKKKSK ISASRKLQLK TLLLQIAKQE 
LEREAEERRG EKGRALSTRC QPLELAGLGF AELQDLCRQL HARVDKVDEE RYDIEAKVTK 
NITEIADLTQ KIFDLRGKFK RPTLRRVRIS ADAMMQALLG ARAKESLDLR AHLKQVKKED 
TEKENREVGD WRKNIDALSG MEGRKKKFES