Alternative titles; symbols
HGNC Approved Gene Symbol: TNNI3
Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38) : 19:55,151,767-55,157,732 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
19q13.42 | ?Cardiomyopathy, dilated, 2A | 611880 | Autosomal recessive | 3 |
Cardiomyopathy, dilated, 1FF | 613286 | 3 | ||
Cardiomyopathy, familial restrictive, 1 | 115210 | Autosomal dominant | 3 | |
Cardiomyopathy, hypertrophic, 7 | 613690 | Autosomal dominant | 3 |
Troponin I (TnI) is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle; see also TNNI1 (191042). The others are troponin T (TnT; see 191041) and troponin C (TnC; see 191040).
Vallins et al. (1990) cloned a full-length cDNA for the human cardiac muscle troponin I. The deduced protein contains 210 amino acids. Northern blot analysis detected TNNI3 expression in 20-week fetal heart, 28-week fetal heart, 9-month postnatal heart, and adult ventricular muscle, but not in adult skeletal muscle.
Joyce et al. (2024) noted that cardiac troponin, TNNI3, is distinguished from its skeletal muscle paralogs, TNNI1 (191042) and TNNI2 (191043), by the presence of a regulatory 32-amino acid N-terminal extension that harbors 2 phosphorylatable serines, ser23 and ser24. Phosphorylation of ser23 and ser24 defends diastolic filling by means of an increased cardiomyocyte relaxation rate.
Bhavsar et al. (1996) showed that the TNNI3 gene contains 8 exons and spans 6.2 kb of genomic DNA. The authors showed that a 2,300-bp block of 5-prime sequence has promoter activity in both cardiac myocytes and skeletal muscle cells but was inactive in fibroblasts, suggesting that this 5-prime region is necessary but not sufficient for cardiac tissue specificity.
MacGeoch et al. (1991), who referred to the gene by the symbol TNNC1, mapped the cardiac troponin I gene to chromosome 19p13.2-q13.2 by analysis of somatic cell hybrids containing various segments of chromosome 19. Bermingham et al. (1995) mapped the TNNI3 gene to chromosome 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. Mogensen et al. (1997) mapped the TNNI3 gene to chromosome 19q13.4 by radiation hybrid mapping.
Barton et al. (1999) determined that the TNNI3 gene and the slow skeletal muscle troponin gene (TNNT1; 191041) are oriented head to tail, with the TNNI3 gene 2.6 kb upstream of exon 1 of the TNNT1 gene.
By interspecific backcross analysis, Bermingham et al. (1995) assigned the mouse homolog (Tnni3) to a site close to the centromere of chromosome 7. Guenet et al. (1996) demonstrated that the Tnni3 gene is located on mouse chromosome 7 in a region of homology to 19q.
Bhavsar et al. (1996) noted that the troponin complex serves as a calcium-sensitive switch that regulates striated muscle contraction. Troponin I binds actin and inhibits actomyosin ATPase activity in the absence of calcium. Cardiac muscle troponin I is expressed only in the heart.
Labarrere et al. (2000) found that persistent elevation of cardiac troponin I levels after heart transplantation were associated with high risk for developing coronary artery disease and graft failure after cardiac transplantation.
Horwich et al. (2003) assayed cardiac troponin I (cTnI) in 238 patients with advanced heart failure but no acute coronary syndrome or myocarditis who were referred for cardiac transplantation. Patients with detectable cTnI levels had significantly higher B-type natriuretic peptide (BNP; 600295) levels (p less than 0.001) and more impaired hemodynamic profiles, including higher pulmonary wedge pressures (p = 0.002) and lower cardiac indexes (p less than 0.0001). A significant correlation was found between detectable cTnI and progressive decline in ejection fraction over time (p less than 0.01), and detectable cTnI was associated with increased mortality risk (relative risk, 2.05; 95% CI, 1.22-3.43) and remained a significant predictor of death even after adjustment for other factors associated with adverse prognosis. Used in conjunction with BNP, cTnI further improved prognostic value. Horwich et al. (2003) concluded that cTnI may be a useful tool in identifying patients with heart failure who are at increased risk for progressive ventricular dysfunction and death.
Using yeast 2-hybrid analysis and protein pull-down assays, Canaider et al. (2006) showed that DSCR1L2 (RCAN3; 605860) and a DSCR1L2 isoform, DSCR1L2-E2E5, bound TNNI3 via an N-terminal domain.
Crystal Structure
Takeda et al. (2003) presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin (see 191010)-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament.
Reviews
Chien (2003) reviewed the molecular defects linked to human cardiomyopathies.
Huang and Du (2004) reviewed the role of TNNI3 in cardiac function, the diastolic dysfunction that results from TNNI3 deficiency, and TNNI3 mutation in restrictive cardiomyopathy.
Hypertrophic Cardiomyopathy 7
Kimura et al. (1997) analyzed the TNNI3 gene in 184 unrelated patients with hypertrophic cardiomyopathy (CMH7; 613690) and identified 6 heterozygous mutations in 6 probands, respectively (see, e.g., 191044.0001 and 191044.0002). Although apical HCM had been associated particularly with CMH4 (115197), Kimura et al. (1997) found that 3 of 36 (8.3%) patients with apical HCM had mutations in the TNNI3 gene. In addition, all 3 individuals with G203S mutation in the TNNI3 gene (191044.0014) exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; 194200); Kimura et al. (1997) noted that although a locus for 'CMH with WPW' had been mapped to chromosome 7q3 (CMH6; 600858), their findings indicated that more than 1 form of CMH is associated with WPW syndrome.
Restrictive Cardiomyopathy 1
Mogensen et al. (2003) studied a family segregating both hypertrophic cardiomyopathy and restrictive cardiomyopathy (RCM1; 115210). Linkage analysis of recognized CMH genes identified TNNI3 as the likely disease gene. Mutation analysis of TNNI3 by direct sequencing identified an asp190-to-gly substitution (D190G; 191044.0005), which was incorrectly reported as an asp190-to-his substitution, that segregated with the disease in the family (maximum 2-point lod score = 4.8). Analysis of TNNI3 was performed in an additional 9 unrelated patients with idiopathic RCM, 6 of whom were shown to carry TNNI3 mutations (e.g., 191044.0006-191044.0008).
Dilated Cardiomyopathy 2A
Using a candidate gene approach, Murphy et al. (2004) analyzed the TNNI3 gene in 235 consecutive patients with dilated cardiomyopathy (CMD; see CMD2A, 611880) and identified homozygosity for a missense mutation (A2V; 191044.0009) in a man who had undergone cardiac transplantation at 28 years of age. His affected sister was also homozygous for the mutation; the unaffected parents and an unaffected sister were heterozygotes. Functional studies of the A2V mutant cTnI showed impairment of troponin interactions.
Dilated Cardiomyopathy 1FF
Carballo et al. (2009) analyzed the TNNI3 gene in 96 probands with dilated cardiomyopathy in whom screening for mutations in 6 more commonly implicated CMD genes was negative and identified heterozygosity for respective missense mutations (191044.0012-191044.0013) in the TNNI3 gene in 2 probands with severe, early-onset CMD (CMD1FF; 613286). Functional analysis revealed that troponin reconstituted with either mutant had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal.
Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (191044.0012), gly159 to asp in TNNC1 (191040.0001)), and glu1426 to lys in MYH7 (160760), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM.
Using actomyosin ATPase assays, Gomes et al. (2005) showed that wildtype human cTnI inhibited ATPase activity in a concentration-dependent manner. However, cTnI with any of 5 mutations associated with restrictive cardiomyopathy (RCM1; 115210), leu144 to gln (L144Q; 191044.0011), ala171 to thr (A171T; 191044.0010), arg192 to his (R192H; 191044.0006), lys178 to glu (K178E; 191044.0007), and arg145 to trp (R145W; 191044.0008), showed reduced ability to inhibit ATPase activity in the absence of Ca(2+). Mixing wildtype and mutant cTnIs in actomyosin ATPase assays in the absence of Ca(2+) revealed that L144Q, A171T, and R192H were dominant over wildtype cTnI, whereas K178E was equivalent to wildtype cTnI, and R145W was weaker than wildtype cTnI. The L144Q, R145W, and K178E mutants were unable to fully relax contraction in porcine skinned fibers in the absence of Ca(2+). The 2 mutants that showed the greatest inability to inhibit ATPase activity, L144Q and R145W, also showed the worst ability to inhibit force development in porcine fibers at basal Ca(2+) levels. All 5 mutants showed an increase in the Ca(2+) sensitivity of force development compared with wildtype cTnI. The 2 mutants associated with the worst clinical phenotype, K178E and R192H, showed large increases in Ca(2+) sensitivity. Gomes et al. (2005) concluded that mutations in cTnI associated with restrictive cardiomyopathy result in increased Ca(2+) sensitivity of force development and also affect basal and maximal force and basal and maximal actomyosin ATPase activity.
Joyce et al. (2024) determined that the 32-amino acid N-terminal extension of cardiac Tnni3 was lost during evolution in shrew and mole lineages due to exon-3 inactivation. An exception was Pyrenean desman, as exon 3 was intact and had the potential to encode ser23 and ser24. However, despite being intact, exon 3 was not present in Tnni3 mRNA in desmans, likely because desman exon 3 evolved under purifying selection and may be alternatively spliced out and skipped. The Tnni3 N-terminal extension was also intact in bats, a family related to shrew and mole lineages with exceptionally high heart rates. However, cardiac Tnni3 exon 3 was alternatively spliced and skipped in bats. As a results, exon 3 was not translated in bats, and the variant isoform was incorporated into cardiac myofibrils, supporting possible alternative splicing of exon 3 in desmans. These results suggested that skipping exon 3 during evolution to mimic ser23 and ser24 phosphorylation in cardiac Tnni3 without adrenergic stimulation might be a mechanism to improve diastolic filling and facilitate evolution of exceptionally high resting heart rates.
In affected members of a large multigenerational Korean family with hypertrophic cardiomyopathy-7 (CMH7; 613690), Kimura et al. (1997) identified a CGG-to-GGG nucleotide change in the TNNI3 gene, resulting in an arg145-to-gly (R145G) substitution at a conserved residue.
Lang et al. (2002) showed that the R145G mutation impairs force development and relaxation. These intrinsic contractile changes would likely result in diastolic dysfunction in vivo. Hypertrophy could arise as a compensatory mechanism.
Wen et al. (2008) found that skinned papillary fibers from transgenic mice expressing human cTnI with the R145G mutation (Tg-R145G mice) developed significantly decreased maximal Ca(2+)-activated force without changes in maximal ATPase activity compared with transgenic mice expressing wildtype human cTnI (Tg-WT mice). Tg-R145G fibers showed increased Ca(2+) sensitivity in both ATPase and force development compared with Tg-WT fibers. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers. Use of a myosin ATPase inhibitor showed that R145G impaired the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Furthermore, electrical stimulation caused prolonged force and intracellular Ca(2+) concentration transients in intact Tg-R145G papillary muscles compared with Tg-WT papillary muscles. Wen et al. (2008) concluded that hypertrophic cardiomyopathy due to the R145G mutation is likely caused by compensatory changes activated by higher energy cost of cross-bridge formation, slowed rate of fiber relaxation, and the inability of cardiac fibers to completely relax in the absence of Ca(2+).
In a Japanese male patient with sporadic hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for an A-C transversion in exon 8 of the TNNI3 gene, resulting in a lys206-to-gln (K206Q) substitution at a highly conserved residue. The mutation was not found in the unaffected parents.
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom they found a missense mutation in the TNNI3 gene. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a C-to-T transition in exon 5, replaced proline with serine at amino acid position 82 (P82S). Proline-82 is highly conserved in mammalian, avian, and amphibian troponin I molecules.
In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous P82S mutation in the TNNI3 gene and a heterozygous missense mutation in the MYH7 gene (160760.0043). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation, whereas her as yet unaffected 13-year-old son carried only the TNNI3 P82S variant. Frazier et al. (2008) suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy.
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom a missense mutation in TNNI3 was found. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a G-to-A transition in exon 8, replaced aspartic acid with asparagine at amino acid position 196 (D196R). Aspartic acid-196 is highly conserved in mammalian, avian, and amphibian troponin I molecules.
In a family with both hypertrophic cardiomyopathy-7 (CMH7; 613690) and restrictive cardiomyopathy-1 (RCM1; 115210), Mogensen et al. (2003) identified an 87A-G nucleotide transition in exon 8 of the TNNI3 gene, resulting in an asp190-to-gly substitution (D190G), that segregated with the disease (maximum 2-point lod score = 4.8). (Mogensen et al. (2003) originally referred to the mutation as asp190 to his, which they later corrected in an erratum.) The mutation was not found in 200 chromosomes from Caucasian control individuals. There were a significant number of premature sudden deaths in the family, suggesting that the R190G substitution is associated with an adverse phenotype. Asp190 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin I (Perry, 1999).
In an individual with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a de novo 93G-A transition in exon 8 of the TNNI3 gene, resulting in an arg192-to-his (R92H) substitution. (Mogensen et al. (2003) originally referred to the transition as 92C-A, which they later corrected in an erratum.) Arg192 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin (Perry, 1999).
In a young individual with idiopathic restrictive cardiomyopathy (RCM1;115210), Mogensen et al. (2003) identified a de novo 886A-G transition in exon 7 of the TNNI3 gene, resulting in a lys178-to-glu (K178E) substitution. Amino acids 173-181 bind to actin and increase the inhibitory effect of troponin I (Perry, 1999).
In 2 unrelated individuals with typical features of restrictive cardiomyopathy (RCM1; 115210) diagnosed in their late fifties, Mogensen et al. (2003) identified a 799C-T transition in the TNNI3 gene, resulting in an arg145-to-trp (R145W) substitution. The sequence required for inhibition of human cardiac troponin I actomyosin ATPase activity consists of 21 amino acid residues (137-148) (Perry, 1999). Haplotype analysis with respect to the TNNI3 locus on chromosome 19 did not suggest a common founder effect.
In a brother and sister from a family with dilated cardiomyopathy (CMD2A; 611880), Murphy et al. (2004) identified homozygosity for a 4C-T transition in exon 1 of the TNNI3 gene, resulting in an ala2-to-val (A2V) substitution. The unaffected parents and an unaffected sister were heterozygous for the mutation. The parents were unaware of any familial relationship, but analysis of microsatellite markers around the TNNI3 locus showed that they shared the same haplotype of the mutated allele, indicating remote consanguinity. Functional studies showed significant impairment of mutant TNNI3 and wildtype TNNT2 protein interaction.
Carballo et al. (2009) stated that in their analysis of the effect of the A2V mutation on ATPase regulation, troponin function was not significantly altered.
In a woman with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a T-to-A transversion at nucleotide 797 in exon 7 of the TNNI3 gene, resulting in a leu144-to-gln (L144Q) substitution. The patient developed symptoms of heart failure at the age of 17 years, and she died of heart failure at the age of 31 years awaiting cardiac transplantation. Several members of her family had died suddenly, but were not available for investigation.
In a man with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a G-to-A transition at nucleotide 856 in exon 7 of the TNNI3 gene, resulting in an ala171-to-thr (A171T) substitution. The patient was diagnosed in his late fifties following an embolic stroke. He was an only child, and no clinical data or DNA was available on his deceased parents. Subsequent mutation analysis of his children did not reveal further carriers.
In a father and 2 sons with dilated cardiomyopathy (CMD1FF; 613286), Carballo et al. (2009) identified heterozygosity for a 106A-C transversion in exon 3 of the TNNI3 gene, resulting in a lys36-to-gln (K36Q) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with K36Q had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The father and 1 son had rapidly progressive disease, requiring cardiac transplantation soon after diagnosis at ages 15 years and 6 years, respectively; screening of the other mutation-positive son revealed mild CMD with mildly reduced systolic contractility. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and 3 brothers; ECG and echocardiography in the mother and 1 brother confirmed normal cardiac function. Haplotype analysis indicated that the proband inherited the mutation from his father, who died in a traffic accident at age 50 years with no known cardiac disease.
Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins, including K36Q in TNNI3, and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM.
In a man who was diagnosed at age 24 years with severe dilated cardiomyopathy (CMD1FF; 613286), requiring implantation of a left ventricular assist device within 2 months and undergoing cardiac transplantation 13 months later, Carballo et al. (2009) identified heterozygosity for a 555C-G transversion in exon 7 of the TNNI3 gene, resulting in an asn185-to-lys (N185K) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with N185K had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and brother, who had normal ECGs and echocardiograms. However, it was detected in a stored DNA sample from his father, who was diagnosed with CMD at 50 years of age and died 4 years later from complications related to cardiac resynchronization therapy.
In a Japanese mother and her son and daughter with hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for a G-A transition in exon 8 of the TNNI3 gene, resulting in a gly203-to-ser (G203S) substitution at a highly conserved residue. The affected individuals in this family had cardiac hypertrophy only at the apex (apical CMH), and all 3 also exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; 194200).
In a Japanese father and son with hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for a 3-bp deletion (delAAG) in exon 7 of the TNNI3 gene, resulting in deletion of a lys residue at codon 183 (L183). The father had cardiac hypertrophy only at the apex (apical CMH), whereas the son had ventricular hypertrophy typical of CMH.
In a proband who was found to have apical hypertrophy (CMH7; 613690) after presenting with atrial fibrillation, Arad et al. (2005) identified a heterozygous arg21-to-cys (R21C) mutation in the TNNI3 gene. The proband's father, 3 sibs, and her 18-year-old daughter all had sudden cardiac death. Clinical evaluation of 3 other mutation carriers in the family revealed that 1 had asymmetric septal hypertrophy, another had isolated left atrial enlargement, and the third had normal cardiac dimensions despite an abnormal electrocardiogram. Arad et al. (2005) stated that they also identified the R21C mutation in another CMH family, in which 4 patients had subaortic asymmetric hypertrophy and 1 mutation carrier with normal cardiac dimensions was resuscitated from sudden cardiac death.
Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112: 2805-2811, 2005. [PubMed: 16267253] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.547448]
Barton, P. J. R., Cullen, M. E., Townsend, P. J., Brand, N. J., Mullen, A. J., Norman, D. A. M., Bhavsar, P. K., Yacoub, M. H. Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T. Genomics 57: 102-109, 1999. [PubMed: 10191089] [Full Text: https://doi.org/10.1006/geno.1998.5702]
Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C. Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse. Genomics 30: 620-622, 1995. [PubMed: 8825654] [Full Text: https://doi.org/10.1006/geno.1995.1288]
Bhavsar, P. K., Brand, N. J., Yacoub, M. H., Barton, P. J. R. Isolation and characterization of the human cardiac troponin I gene (TNNI3). Genomics 35: 11-23, 1996. [PubMed: 8661099] [Full Text: https://doi.org/10.1006/geno.1996.0317]
Canaider, S., Facchin, F., Griffoni, C., Casadei, R., Vitale, L., Lenzi, L., Frabetti, F., D'Addabbo, P., Carinci, P., Zannotti, M., Strippoli, P. 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 372: 128-136, 2006. [PubMed: 16516408] [Full Text: https://doi.org/10.1016/j.gene.2005.12.029]
Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H. Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy. Circ. Res. 105: 375-382, 2009. [PubMed: 19590045] [Full Text: https://doi.org/10.1161/CIRCRESAHA.109.196055]
Chien, K. R. Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies. J. Clin. Invest. 111: 175-178, 2003. Note: Erratum: J. Clin. Invest. 11: 1433 only, 2003. [PubMed: 12531871] [Full Text: https://doi.org/10.1172/JCI17612]
Frazier, A., Judge, D. P., Schulman, S. P., Johnson, N., Holmes, K. W., Murphy, A. M. Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations. Pediat. Cardiol. 29: 846-850, 2008. [PubMed: 18175163] [Full Text: https://doi.org/10.1007/s00246-007-9177-9]
Gomes, A. V., Liang, J., Potter, J. D. Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development. J. Biol. Chem. 280: 30909-30915, 2005. [PubMed: 15961398] [Full Text: https://doi.org/10.1074/jbc.M500287200]
Guenet, J.-L., Simon-Chazottes, D., Gravel, M., Hastings, K. E. M., Schiaffino, S. Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse chromosomes 1 and 7. Mammalian Genome 7: 13-15, 1996. [PubMed: 8903721] [Full Text: https://doi.org/10.1007/s003359900004]
Horwich, T. B., Patel, J., MacLellan, W. R., Fonarow, G. C. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation 108: 833-838, 2003. [PubMed: 12912820] [Full Text: https://doi.org/10.1161/01.CIR.0000084543.79097.34]
Huang, X., Du, J. Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy. Acta Pharm. Sin. 25: 1569-1575, 2004. [PubMed: 15569399]
Joyce, W., He, K., Zhang, M., Ogunsola, S., Wu, X., Joseph, K. T., Bogomolny, D., Yu, W., Springer, M. S., Xie, J., Signore, A. V., Campbell, K. L. Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades. Science 385: 1466-1471, 2024. [PubMed: 39325895] [Full Text: https://doi.org/10.1126/science.adi8146]
Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nature Genet. 16: 379-382, 1997. [PubMed: 9241277] [Full Text: https://doi.org/10.1038/ng0897-379]
Labarrere, C. A., Nelson, D. R., Cox, C. J., Pitts, D., Kirlin, P., Halbrook, H. Cardiac-specific troponin I levels and risk of coronary artery disease and graft failure following heart transplantation. JAMA 284: 457-464, 2000. [PubMed: 10904509] [Full Text: https://doi.org/10.1001/jama.284.4.457]
Lang, R., Gomes, A. V., Zhao, J., Housmans, P. R., Miller, T., Potter, J. D. Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. J. Biol. Chem. 277: 11670-11678, 2002. [PubMed: 11801593] [Full Text: https://doi.org/10.1074/jbc.M108912200]
MacGeoch, C., Barton, P. J. R., Vallins, W. J., Bhavsar, P., Spurr, N. K. The human cardiac troponin I locus: assignment to chromosome 19p13.2-19q13.2. Hum. Genet. 88: 101-104, 1991. [PubMed: 1959915] [Full Text: https://doi.org/10.1007/BF00204938]
Mogensen, J., Kruse, T. A., Borglum, A. D. Assignment of the human cardiac troponin I gene (TNNI3) to chromosome 19q13.4 by radiation hybrid mapping. Cytogenet. Cell Genet. 79: 272-273, 1997. [PubMed: 9605869] [Full Text: https://doi.org/10.1159/000134740]
Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003. [PubMed: 12531876] [Full Text: https://doi.org/10.1172/JCI16336]
Murphy, R. T., Mogensen, J., Shaw, A., Kubo, T., Hughes, S., McKenna, W. J. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. (Letter) Lancet 363: 371-372, 2004. [PubMed: 15070570] [Full Text: https://doi.org/10.1016/S0140-6736(04)15468-8]
Niimura, H., Patton, K. K., McKenna, W. J., Soults, J., Maron, B. J., Seidman, J. G., Seidman, C. E. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 105: 446-451, 2002. [PubMed: 11815426] [Full Text: https://doi.org/10.1161/hc0402.102990]
Perry, S. V. Troponin I: inhibitor or facilitator. Molec. Cell Biochem. 190: 9-32, 1999. [PubMed: 10098965]
Takeda, S., Yamashita, A., Maeda, K., Maeda, Y. Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature 424: 35-41, 2003. [PubMed: 12840750] [Full Text: https://doi.org/10.1038/nature01780]
Vallins, W. J., Brand, N. J., Dabhade, N., Butler-Browne, G., Yacoub, M. H., Barton, P. J. R. Molecular cloning of human cardiac troponin I using polymerase chain reaction. FEBS Lett. 270: 57-61, 1990. [PubMed: 2226790] [Full Text: https://doi.org/10.1016/0014-5793(90)81234-f]
Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B. Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018. [PubMed: 29093449] [Full Text: https://doi.org/10.1038/s41598-017-13675-8]
Wen, Y., Pinto, J. R., Gomes, A. V., Xu, Y., Wang, Y., Wang, Y., Potter, J. D., Kerrick, W. G. L. Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice. J. Biol. Chem. 283: 20484-20494, 2008. [PubMed: 18430738] [Full Text: https://doi.org/10.1074/jbc.M801661200]