| *191041 | ||||||||||||||||||||||||||||||||||||
| TROPONIN T1, SKELETAL, SLOW; TNNT1 | ||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||
| TROPONIN T | ||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: TNNT1 | ||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 19q13.42 Genomic coordinates (GRCh37): 19:55,644,160 - 55,660,605 (from NCBI) | ||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||
| Barton et al. (1999) determined that the TNNT1 gene contains 14 exons and spans more than 16 kb. The first exon is noncoding. | ||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||
| Johnston et al. (2000) demonstrated that a form of autosomal recessive nemaline myopathy, Amish nemaline myopathy (ANM; 605355), is caused by mutation in troponin T1 (see 191041.0001). | ||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||
| .0001 NEMALINE MYOPATHY, 5 | ||||||||||||||||||||||||||||||||||||
| TNNT1, GLU180TER [dbSNP:rs80358249] | ||||||||||||||||||||||||||||||||||||
| In affected individuals with Amish nemaline myopathy (605355), Johnston et al. (2000) found a 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. 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 detected 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. | ||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||
| Trask et al. (1993) | ||||||||||||||||||||||||||||||||||||
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