Alternative titles; symbols
HGNC Approved Gene Symbol: TNNC1
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38): 3:52,451,100-52,454,041 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.1 | Cardiomyopathy, dilated, 1Z | 611879 | Autosomal dominant | 3 |
| Cardiomyopathy, hypertrophic, 13 | 613243 | Autosomal dominant | 3 |
Contraction in striated muscle is regulated by the calcium-ion-sensitive, multiprotein complex troponin and the fibrous protein tropomyosin (see 191010). As a result of calcium-ion uptake by troponin C, the elements of the muscle thin filament undergo a series of allosteric changes which allow the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Roher et al. (1986) reported the primary structure (amino acid sequence) of troponin C from human cardiac muscle; it consists of 161 amino acid residues. Comparison with the sequences in the rabbit and the ox shows that troponin C is one of the most highly conserved proteins known. Romero-Herrera et al. (1976) established the primary structure of human skeletal muscle troponin C. They found only a single amino acid difference between rabbit and human skeletal muscle troponin C and possibly only a single amino acid change between human skeletal troponin C and bovine cardiac muscle troponin C. Thus, they concluded that cardiac and slow-twitch skeletal troponin C are presumably identical.
Schreier et al. (1990) described the structure of the TNNC gene. It is 3 kb long, with 6 exons.
Using a human/rodent monochromosomal mapping panel, Song et al. (1996) mapped a human slow-twitch skeletal muscle/cardiac troponin C gene (symbolized TNNC1) to chromosome 3 by PCR. Chromosome 3 somatic cell hybrids with various rearrangements were used for finer mapping to 3p21.3-p14.3.
Bermingham et al. (1995) mapped a gene they symbolized TNNC1 to 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. By interspecific backcross analysis, they mapped the mouse homolog to a site close to the centromere of chromosome 7. Song (1997) indicated that the gene mapped by Bermingham et al. (1995) should not be symbolized TNNC1 since it represented cardiac troponin I (TNNI3; 191044) which had been mapped by others to chromosome 19. Song et al. (1996) mapped the authentic TNNC1 gene to chromosome 3. Using a 'monochromosomal' hybrid panel, Townsend et al. (1997) mapped the TNNC1 gene to chromosome 3; subsequent analysis of the Genebridge 4 radiation hybrid panel localized the gene to 3p in a region consistent with the earlier assignment.
Crystal Structure
Troponin consists of 3 subunits, TnC, TnI (see 191044), and TnT (see 191045), and, together with tropomyosin, is located on the actin filament. 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-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.
Hypertrophic Cardiomyopathy 13
In a German patient with hypertrophic cardiomyopathy (CMH13; 613243), Hoffmann et al. (2001) identified a heterozygous mutation in the TNNC1 gene (L29Q; 191040.0002). The authors stated that they could not determine whether this was a disease-causing variant. Schmidtmann et al. (2005) studied the structural and functional consequences of the L29Q substitution and demonstrated alteration of the dynamics of the actin-myosin interaction as well as impairment of PKA (see 601639)-dependent signaling from cardiac TnI (191044) to cardiac TnC, resulting in an increased sensitivity to Ca(2+) when cardiac TnI is phosphorylated.
Landstrom et al. (2008) analyzed the TNNC1 gene in 1,025 unrelated patients with CMH and identified 4 heterozygous mutations in 4 Caucasian patients (see, e.g., A8V, 191040.0003; C84Y, 191040.0004; D145E, 191040.0005) who were negative for mutation in 15 known CMH-susceptibility genes. Functional studies showed increased Ca(2+) sensitivity of force development and force recovery with 3 of the mutations; the fourth, an E134D substitution, had no effect on the parameters studied.
Pinto et al. (2009) performed a functional and structural analysis of the 4 TNNC1 mutations identified by Landstrom et al. (2008) in CMH patients and found that 3 of them (A8V, C84Y, and D145E) increased the Ca(2+) sensitivity of the filament, but they noted that the effects of the mutations on the Ca(2+) affinity of isolated cardiac TnC, cardiac troponin, and thin filaments were not sufficient to explain the large Ca(2+) sensitivity changes seen in reconstituted and fiber assays. Circular dichroism measurements revealed changes in the secondary structures of the TNNC1 mutants A8V, C84Y, and D145E; Pinto et al. (2009) suggested that these changes in secondary structure might contribute to modified protein-protein interactions along the sarcomere lattice disrupting the coupling between the cross-bridge and Ca(2+) binding to cardiac TnC.
In a 5-year-old boy with CMH and a history of ventricular fibrillation, Parvatiyar et al. (2012) analyzed 12 CMH-associated genes and identified heterozygosity for a missense mutation in the TNNC1 gene (A31S; 191040.0006). Functional analysis suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband.
Dilated Cardiomyopathy 1Z
Mogensen et al. (2004) analyzed the TNNC1 gene in 235 consecutive unrelated probands with dilated cardiomyopathy (see CMD1Z, 611879) and identified heterozygosity for a mutation in the TNNC1 gene (G159D; 191040.0001) in 5 affected members of a 3-generation family with a severe phenotype. Functional studies showed significant alterations in the interaction of the mutated troponin C with wildtype troponins T and I.
Mirza et al. (2005) studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; 191045.0006-191045.0010, respectively), 2 in the TPM1 gene (E54K, 191010.0004; E40K, 191010.0005), and 1 in the TNNC1 gene (G159D). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. Mirza et al. (2005) stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype.
Dyer et al. (2009) performed functional studies of mutant myocytes from an explanted heart with the G159D mutation (191040.0001). The G159D myocytes showed an increased sensitivity to Ca(2+) compared to wildtype TNNC1; however, dephosphorylation of troponin did not produce the expected increase in Ca(2+) sensitivity with the mutant cTnC. Dyer et al. (2009) suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation.
In a cohort of 312 probands with dilated cardiomyopathy, Hershberger et al. (2010) analyzed 5 CMD-associated genes and identified a missense mutation in the TNNC1 gene (M103I; 191040.0008) in 1 proband (D.2) and an affected relative that was not found in 246 control individuals. Another 3 heterozygous TNNC1 missense variants were identified in 3 CMD probands, but segregation data was lacking for those variants.
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), G159D in TNNC1, 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.
By trio whole-exome sequencing in an infant girl with CMD and her unaffected parents, Johnston et al. (2019) identified heterozygosity for a de novo missense mutation in the TNNIC1 gene (I4M; 191040.0009) that was not found in the gnomAD database. Functional analysis showed a reduction in the magnitude and rate of isometric force generation with the mutant, as well as tighter binding between cTnT (TNNT2; 191045) and cTnC.
Using duo whole-exome sequencing in a family in which 3 sibs had severe dilated pediatric cardiomyopathy, Udani et al. (2023) identified a de novo heterozygous missense mutation in the TNNC1 gene (G34R; 191040.0007) in the proband and first stillborn sib. Sanger sequencing identified the mutation in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo variant in all 3 affected sibs suggested germline mosaicism.
In a sister and brother with severe early-onset CMD, Landim-Vieira et al. (2020) identified compound heterozygosity for missense mutations in the TNNC1 gene: the previously reported CMH-associated D145E substitution (191040.0005), and a c.394G-A transition resulting in an asp132-to-asn (D132N) substitution, both occurring at highly conserved residues within the C-domain. No other rare or pathogenic variants were found in other known cardiomyopathy genes in either of the sibs. Their unaffected parents, who were in their fifth decade and had normal echocardiograms, were each heterozygous for 1 of the mutations. Functional analysis using porcine cardiac muscle preparations (CMPs) showed that the D132N variant significantly reduced, whereas the D145E variant significantly increased, myofilament Ca(2+) sensitivity of force generation; and there was no significant difference in Ca(2+) sensitivity of tension when CMPs were reconstituted with a 50-50 mixture of D132N and D145E. Thus the incorporation of both mutants appeared to normalize the opposite effects of the 2 variants on Ca(2+) dependence of isometric force, which the authors noted was difficult to reconcile with the severe CMD pathology associated with the presence of the 2 mutations. The proband was a female infant who from birth had gradually increasing left ventricular enlargement and worsening LV function; she died following cardiac arrest at age 14 months while awaiting transplant. She had an 11-year-old brother who was diagnosed as a neonate with severe CMD and underwent transplantation at 13 months of age. He had good function of the transplanted heart, and no signs of skeletal muscle problems. Their mother had experienced 3 miscarriages with in vitro-fertilized pregnancies, and another sib died after premature live birth at 23 weeks' gestation.
Landim-Vieira et al. (2020) used CRISPR/Cas9-mediated gene editing to knock out TNNC1 in Xenopus. Loss of the TNNC1 gene did not prevent the early stages of development, but resulted in a dramatic cardiac phenotype consistent with dilated cardiomyopathy in the mutant tadpoles, which demonstrated ventricular dilation, wall thinning, and almost imperceptible cardiac motion.
In 5 affected members of a family (family A) with severe dilated cardiomyopathy (CMD1Z; 611879), Mogensen et al. (2004) identified heterozygosity for a missense mutation in the TNNC1 gene, predicted to result in a gly159-to-asp (G159D) substitution at a conserved residue in a domain of the protein constitutively occupied by Ca(2+). The mutation was not found in unaffected family members or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of the mutated troponin C interaction with wildtype troponin T, whereas the interaction with wildtype troponin I was significantly enhanced (p less than 0.0001 for both), indicating an altered regulation of myocardial contractility.
In a 3-year-old boy with severe CMD who underwent cardiac transplantation, who was the nephew of the proband from family A reported by Mogensen et al. (2004), Kaski et al. (2007) identified heterozygosity for the G159D mutation in the TNNC1 gene. Dyer et al. (2009) analyzed the patient's explanted heart tissue and found that mutant cardiac troponin C (cTnC) was expressed approximately equimolar with wildtype cTnC. Although the sarcomeric structure and maximal Ca(2+)-activated force was similar in both mutant and wildtype skinned ventricular myocytes, mutant myocytes exhibited significantly greater Ca(2+) sensitivity than wildtype myocytes. An in vitro motility assay using reconstituted thin filaments confirmed greater Ca(2+) sensitivity with mutant filaments, although maximally activated sliding speed was unchanged. In addition, dephosphorylation of troponin produced the expected increase in Ca(2+) sensitivity with wildtype heart troponin, but almost no change in Ca(2+) sensitivity with mutant heart troponin. Dyer et al. (2009) suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation.
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 G159D in TNNC1, 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 60-year-old German man with hypertrophic cardiomyopathy (CMH13; 613243), Hoffmann et al. (2001) identified an c.86T-A transversion in exon 3 of the TNNC1 gene, leading to a leu29-to-gln (L29Q) substitution at a conserved residue. No family members were available for study. The mutation was not detected in 96 controls, but the authors stated that they could not determine whether this was a disease-causing variant.
Schmidtmann et al. (2005) studied the structural and functional consequences of the L29Q substitution, located at the transition of helix A to the nonfunctional Ca(+2)-binding loop, and observed only minor effects on secondary structure by circular dichroism (CD) spectroscopy. Peptide array experiments demonstrated interaction of the nonphosphorylated cardiac TnI (TNNI3; 191044) arm with cardiac TnC around leu29; this interaction did not occur with the L29Q mutant, whether in the phosphorylated or nonphosphorylated state. In vitro assays revealed that with L29Q, the Ca(2+) sensitivity of the actomyosin subfragment 1-ATPase activity and the mean sliding velocity of thin filaments were no longer affected by protein kinase A (see 601639)-dependent phosphorylation of cTnI. Schmidtmann et al. (2005) concluded that L29Q hinders transduction of the phosphorylation signal from cardiac TnI to cardiac TnC.
In a 37-year-old Caucasian man who was diagnosed at 33 years of age with hypertrophic cardiomyopathy (CMH13; 613243) after presenting with dyspnea, Landstrom et al. (2008) identified heterozygosity for a c.23C-T transition in exon 1 of the TNNC1 gene, resulting in an ala8-to-val (A8V) substitution in the N-helix of the N-terminal domain. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms.
In a 17-year-old Caucasian man who was diagnosed at 8 years of age with hypertrophic cardiomyopathy (CMH13; 613243) after presenting with syncope on exertion, Landstrom et al. (2008) identified heterozygosity for a c.251G-A transition in exon 4 of the TNNC1 gene, resulting in a cys84-to-tyr (C84Y) substitution at the beginning of the central helix. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms.
In a 58-year-old Caucasian man who presented with chest pain at age 57 years and was diagnosed with hypertrophic cardiomyopathy (CMH13; 613243), Landstrom et al. (2008) identified heterozygosity for a c.435C-A transversion in exon 5 of the TNNC1 gene, resulting in an asp145-to-glu (D145E) substitution. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms. The patient had a family history consistent with autosomal dominant CMH, with affected individuals including his maternal grandmother, 3 maternal uncles, and 2 daughters of those maternal uncles, all of whom declined to participate in the study.
In a 5-year-old boy with hypertrophic cardiomyopathy and a history of ventricular fibrillation (CMH13; 613243), Parvatiyar et al. (2012) identified heterozygosity for a c.91G-T transversion in the TNNC1 gene, resulting in an ala31-to-ser (A31S) substitution. The mutation was not found in more than 26,600 reference alleles from apparently healthy controls from a variety of racial and ethnic backgrounds, and the family history was negative for CMH or sudden death, suggesting a de novo mutation. Cardiac troponin-C (cTnC)-depleted porcine cardiac fibers showed increased Ca(2+) sensitivity with the mutant compared to wildtype, with no effect on maximal contractile force generation. In reconstituted thin filaments, the mutant increased the activation of actomyosin ATPase compared to wildtype; however, under relaxing conditions, mutant and wildtype cTnC inhibited the ATPase to the same degree. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. Parvatiyar et al. (2012) suggested that the A31S mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband.
In 3 sibs with severe dilated pediatric cardiomyopathy (CMD1Z; 611879), Udani et al. (2023) identified a c.110G-C transversion (c.110G-C, NM_003280) in the TNNC1 gene, resulting in a gly34-to-arg (G34R) substitution. The mutation was found by duo whole-exome sequencing in the proband and first stillborn sib and by Sanger sequencing in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo mutation in all 3 affected children suggested germline mosaicism.
In a proband (D.2) with dilated cardiomyopathy (CMD1Z; 611879), Hershberger et al. (2010) identified heterozygosity for a c.4291G-A transition (c.4291G-A, NM_003280.1) in exon 4 of the TNNC1 gene, resulting in a met103-to-ile (M103I) substitution at a conserved residue. The mutation was also present in an affected family member, and was not found in 246 control individuals.
Pinto et al. (2011) studied the M103I mutation that was identified in 2 sisters with CMD by Hershberger et al. (2010). Functional studies in porcine papillary skinned fibers showed decreased Ca(2+) sensitivity of force development with the M103I mutant compared to wildtype TNNC1. In addition, the M103I mutant abolished the effect of PKA (see 188830) phosphorylation on Ca(2+) sensitivity, and also decreased the troponin activation properties of the actomyosin ATPase in the presence of Ca(2+). Circular dichroism spectroscopic studies revealed that the M103I mutant decreases the alpha-helical content of cTnC. The authors suggested that the mutation alters the function and/or ability of the myofilament to bind Ca(2+) due to modifications in the cTnC structure.
In an infant girl with dilated cardiomyopathy (CMD1Z; 611879), Johnston et al. (2019) identified heterozygosity for a de novo c.12C-G transversion in exon 1 of the TNNC1 gene, resulting in an ile4-to-met (I4M) substitution at a highly conserved residue within the N-helix. The mutation was not found in her unaffected parents or in the gnomAD database. Reconstitution of the I4M variant in permeabilized porcine cardiac muscle preparations revealed a significant decrease in the magnitude and rate of isometric force generation at physiologic Ca(2+) activation levels with the mutant compared to wildtype cTnC. The authors demonstrated that cardiac troponin T (TNNT2; 191045), in part due through its intrinsically disordered C terminus, directly binds to cTnC, and observed that the mutant displayed tighter binding than wildtype cTnC.
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