Alternative titles; symbols
HGNC Approved Gene Symbol: TNNT1
SNOMEDCT: 1197155007;
Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38): 19:55,132,698-55,149,206 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.42 | Nemaline myopathy 5A, autosomal recessive, severe infantile | 605355 | Autosomal recessive | 3 |
| Nemaline myopathy 5B, autosomal recessive, childhood-onset | 620386 | Autosomal recessive | 3 | |
| Nemaline myopathy 5C, autosomal dominant | 620389 | Autosomal dominant | 3 |
The TNNT1 gene encodes the slow skeletal muscle troponin. The sarcomere, the contractile element in muscle, including the myocardium, is constituted by 7 major proteins and several minor ones organized into thin and thick filaments. Each tropomyosin dimer (TPM1, 191010; TPM2, 190990) interacts with 7 actins and is associated with a troponin complex. Each complex is composed of 1 molecule of each of the 3 troponins: T, C, and I. This tropomyosin-troponin complex is responsible for the calcium sensitivity of the contractile apparatus (Nadal-Ginard and Mahdavi, 1989), and thus plays an important role in linking excitation to contraction in skeletal muscle.
Samson et al. (1994) concluded that there are 4 isoforms of human slow skeletal troponin-T mRNA and that these probably result from combinatorial alternative splicing of a single gene.
By PCR of adult human skeletal muscle total RNA, Barton et al. (1999) cloned full-length TNNT1 and identified 3 shorter splice variants. The full-length protein contains 278 amino acids. Northern blot analysis detected TNNT1 expression in adult skeletal muscle, but not in adult heart and liver or in fetal heart.
Alternative splicing of exon 5 of the TNNT1 gene generates a high molecular weight (HMW) isoform (with exon 5) and a low molecular weight isoform (LMW) isoform (without exon 5). LMW TNNT1 has a higher binding affinity for tropomyosin and generates more calcium-activated contractile force than the HMW isoform, which enables regulation and modulation of muscle contractility. Normal adult slow muscles express mainly the HMW isoform (summary by Holling et al., 2022).
Barton et al. (1999) determined that the TNNT1 gene contains 14 exons and spans more than 16 kb. The first exon is noncoding.
Samson et al. (1990) assigned the slow skeletal isoform of troponin T (TNNT1) to chromosome 19q13.3-q13.4 using a panel of somatic cell hybrids and a cDNA clone as probe.
Novelli et al. (1991, 1992) confirmed the assignment of the TNNT1 gene to human chromosome 19 by showing the presence of a specific PCR product in hybrids retaining chromosome 19. The cardiac isoform of troponin-I (TNNI3; 191044) maps to the same region.
Samson et al. (1991) achieved regional assignment to the 19q13.2-qter region by analysis of 7 somatic cell hybrids containing different portions of chromosome 19. They excluded TNNT1 as a candidate gene for myotonic dystrophy (DM1; 160900) by the finding of obligate recombination events in family linkage studies.
Samson et al. (1992) mapped the TNNT1 gene to chromosome 19q13.4 by study of somatic cell hybrids and fluorescence in situ hybridization.
Barton et al. (1999) determined that the TNNI3 gene and the TNNT1 gene are oriented head to tail, with the TNNI3 gene 2.6 kb upstream of exon 1 of the TNNT1 gene.
Autosomal Recessive Severe Infantile Nemaline Myopathy 5A
In Amish patients with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), Johnston et al. (2000) identified homozygosity for a nonsense mutation in the TNNT1 gene (E180X; 191041.0001).
In a Dutch boy with NEM5A, van der Pol et al. (2014) identified compound heterozygous mutations in the TNNT1 gene: a splice site mutation (191041.0002) and an intragenic deletion (ex14del; 191041.0003). The mutations were inherited from the unaffected parents. Homozygosity for the splice site mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency.
In 3 unrelated patients with NEM5A, Geraud et al. (2021) identified homozygous or compound heterozygous mutations in the TNNT1 gene (see, e.g., 191041.0004-191041.0006). Western blot analysis of skeletal muscle from the patients showed absence of the TNNT1 protein. All died by 29 months of age.
Autosomal Recessive Childhood-Onset Nemaline Myopathy 5B
In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Pellerin et al. (2020) identified a homozygous missense mutation in the TNNT1 gene (L96P; 191041.0007). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight TNNT1 isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1.
In 2 brothers, born of unrelated Korean parents, with NEM5B, Lee et al. (2022) identified compound heterozygosity for a missense mutation (A242P; 191041.0008) and a splice site mutation (191041.0009) in the TNNT1 gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was demonstrated to result in altered splicing and frameshifts, and the A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that both mutations caused a loss of function.
In a 51-year-old man with NEM5B, Martin-Jimenez et al. (2022) detected homozygosity for a variant in the TNNT1 gene (c.551_552delinsCA) that resulted in an arg184-to-pro (R184P) substitution. The variant was absent from gnomAD. Segregation studies and functional studies were not performed. The patient presented at age 50 years with a respiratory infection followed by respiratory arrest requiring intubation. He subsequently developed muscle weakness in all limbs which was slowly progressive and resulted in difficulty climbing stairs.
Autosomal Dominant Nemaline Myopathy 5C
In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; 620389) originally reported by Spiro and Kennedy (1965) and Gonatas et al. (1966), Konersman et al. (2017) identified a heterozygous missense mutation in the TNNT1 gene (E104V; 191041.0010). The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. Holling et al. (2022) stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; 191030), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium.
In a mother and son with NEM5C, Holling et al. (2022) identified a heterozygous missense mutation in the TNNT1 gene (D65A; 191041.0011) that occurred within the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, whereas coimmunoprecipitation studies showed significantly increased binding of the D65A variant to TPM3 compared to controls, both in the presence and absence of calcium.
Fox et al. (2018) described muscle features in 2 mouse models of Tnnt1 deficiency: a targeted gene knockout (Tnnt1 -/-) model and a site-specific knock-in (Tnnt1 c.505G-T) model. Quadratus femoris muscle tissue showed absence of Tnnt1, atrophy/hypotrophy of small type 1 myofibers, hypertrophy of fast type 2 fibers, and the presence of nemaline rods in both mouse models. Both models also showed impaired muscle force generation and exercise recovery in soleus muscles.
Pellerin et al. (2020) found that morpholino knockout of the tnnt1 gene in zebrafish caused reduced muscle mass, reduced birefringence, and severe truncal curvature compared to controls. Myofibers were disorganized and showed corelike intramyofibrillar areas of sarcomeric disorganization and Z-line thickening. These defects could be rescued by expression of wildtype human TNNT1 mRNA.
In affected individuals with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), also known as Amish nemaline myopathy, Johnston et al. (2000) identified a homozygous c.579G-T transversion in exon 11 of the TNNT1 gene, resulting in a stop codon at amino acid 180 (E180X) and loss of 83 C-terminal residues. Johnston et al. (2000) had treated or obtained clinical information on 71 infants and young children from 33 nuclear Amish families with this form of nemaline myopathy. In the first months of life, affected infants had tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity developed before the children died of respiratory insufficiency, usually in the second year.
Variant Function
Jin et al. (2003) found complete loss of the TNNT1 protein in patients with the E180X mutation. The truncated protein results in elimination of the C-terminal T2 domain that interacts with troponin C (TNNC1; 191040), I (TNNI2; 191043), and tropomyosin (TPM1; 191010), but was predicted to retain a central tropomyosin-binding site that participates in the anchoring of troponin complex to the thin actin filament. If residual truncated protein was produced, this could potentially result in a dominant-negative effect. The significant muscle atrophy observed in the disorder was consistent with the slow Tnt isoform being involved in muscle development and growth.
In a patient with Amish nemaline myopathy due to the E180X mutation, Wang et al. (2005) detected residual mutant TNNT1 mRNA in muscle tissue but no corresponding translated mutant TNNT1 protein. In vitro functional expression studies in nonmuscle cells showed that E180X-mutant protein could be produced but was not detectable when expressed in muscle cells in vitro. The findings suggested rapid degradation of E180X-mutant protein in muscle cells, rather than a loss of nonsense mRNA to explain the absence of a dominant effect. Wang et al. (2005) postulated that inefficient incorporation of mutant TNNT1 into myofilaments results in its degradation by the muscle cell as a protective mechanism.
In a Dutch boy with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), van der Pol et al. (2014) identified compound heterozygous mutations in the TNNT1 gene: a G-to-A transition in intron 8 (c.309+1G-A, NM_003283.4) inherited from the unaffected father, and an exon 14 deletion (ex14del; 191041.0003) inherited from the unaffected mother. Homozygosity for the c.309+1G-A mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency. The splicing defect resulted in the skipping of exon 8 with an in-frame deletion of 39 functionally important residues from the TNNT1 troponin domain (Asp65_Ile103del). The mutations were predicted to result in a loss of function, although the authors noted that the predicted transcripts could be translated into shortened proteins with some residual activity.
For discussion of the exon 14 deletion (ex14del, NM_003283.4) in the TNNT1 gene that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) by van der Pol et al. (2014), see 191041.0002.
In a female infant (patient 2) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) resulting in death at 16 months of age, Geraud et al. (2021) identified compound heterozygous mutations in the TNNT1 gene: a c.334G-T transversion (c.334G-T, NM_003283.5), resulting in a glu112-to-ter (E112X) substitution, and a C-to-A transversion in intron 4 (c.74-67C-A; 191041.0005), predicted to result in a splicing defect. Western blot analysis of skeletal muscle from the patient showed absence of the TNNT1 protein. She had a severe form of the disorder with tongue fasciculations, kyphosis, pectus carinatum, and hypotonia.
For discussion of the c.74-67C-A mutation (c.74-67C-A, NM_003283.5) in intron 4 of the TNNT1 gene, resulting in a splicing defect, that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) by Geraud et al. (2021) see 191041.0004.
In a patient (patient 3) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) resulting in death at 6 months of age, Geraud et al. (2021) identified a homozygous c.16G-T transversion (cc.74-67C-A, NM_003283.5) in the TNNT1 gene, resulting in a glu6-to-ter (E6X) substitution. Western blot analysis of patient skeletal muscle showed absence of the TNNT1 protein.
In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Pellerin et al. (2020) identified a homozygous c.287T-C transition (c.287T-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in a leu96-to-pro (L96P) substitution at a conserved residue. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was predicted to disrupt the alpha-helical secondary structure of the tropomyosin-binding site 1 and impair binding affinity. The mutant protein was likely to be misincorporated into myofilaments and undergo partial degradation, as evidenced by lower levels of the high molecular weight troponin T isoform in patient muscle; low molecular weight isoforms were retained. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1.
Variant Function
Holling et al. (2022) found that expression of the L96P mutation was increased compared to controls when transfected into HEK293 cells. Coimmunoprecipitation studies showed significantly reduced interaction (by 88%) of the L96P mutant with tropomyosin-3 (TPM3; 191030), and this interaction was abrogated in the presence of calcium.
In 2 brothers, born of unrelated Korean parents, with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Lee et al. (2022) identified compound heterozygous mutations in the TNNT1 gene: a c.724G-C transversion (c.724G-C, NM_003283) in exon 12, resulting in an ala242-to-pro (A242P) substitution in the conserved troponin I-binding domain, and a G-to-A transition in intron 11 (c.611+1G-A; 191041.0009), resulting in a splicing defect and frameshifts. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was found once in the heterozygous state in a Korean individual in gnomAD (1 of 249,306 alleles, frequency of 4.01 x 10(-6)). The A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that this mutation causes a loss of function.
For discussion of the G-to-A transition in intron 11 of the TNNT1 gene (c.611+1G-A, NM_003283), resulting in a splicing defect and frameshifts, that was found in compound heterozygous state in 2 brothers with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386) by Lee et al. (2022), see 191041.0008.
In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; 620389) originally reported by Spiro and Kennedy (1965) and Gonatas et al. (1966), Konersman et al. (2017) identified a heterozygous c.311A-T transversion (c.311A-T, NM_003283.4) in exon 9 of the TNNT1 gene, resulting in a glu104-to-val (E104V) substitution at a highly conserved residue in the tropomyosin-binding site 1 region. The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. It was not present in public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Muscle samples from 2 patients showed normal levels of the TNNT1 protein, although low molecular weight (LMW) TNNT1 transcripts and protein levels were increased compared to controls, suggesting a compensatory mechanism. The authors postulated that the mutation could affect the affinity of TNNT1 for tropomyosin.
Variant Function
Holling et al. (2022) stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; 191030), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium.
In a mother and son with autosomal dominant nemaline myopathy-5C (NEM5C; 620389), Holling et al. (2022) identified a heterozygous c.194A-C transversion (c.194A-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in an asp65-to-ala (D65A) substitution in the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Genetic studies of the mother's parents showed that the mutation occurred de novo in the mother. The total amount of TNNT1 protein in the mother's skeletal muscle was similar to controls. Muscle biopsy from the mother showed type 1 fiber hypotrophy, type 2 fiber hypertrophy, increased amounts of fast skeletal fiber myosin-2a (MYH2; 160740), and increased actin levels, which may be compensatory mechanisms. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, and coimmunoprecipitation studies showed significantly increased binding to tropomyosin-3 (TPM3; 191030), both in the presence and absence of calcium.
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