HGNC Approved Gene Symbol: TNNT3
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,919,552-1,938,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Arthrogryposis, distal, type 2B2 | 618435 | Autosomal dominant | 3 |
The contraction of striated muscle is initiated by the binding of intracellular calcium to the troponin complex located in the thin filaments. The complex consists of the 3 different troponins, designated troponin C (e.g., 191039), troponin T (e.g., 191041), and troponin I (e.g., 191042). The troponin T subunit binds the complex to tropomyosin (191010). The troponin T proteins occur as multiple isoforms that are encoded by different members of a multigene family, all of which undergo alternative splicing (see also 191045). The fast skeletal troponin T genes (also symbolized TNTF by Wu et al., 1994) have been characterized in various species and have been shown to produce isoforms as a consequence of differential splicing of any of 5 exons (exons 4-8) at the 5-prime end of the gene or of exon 16 (or alpha) and 17 (or beta) at the 3-prime end of the gene. The alpha and beta isoforms differ in 14 amino acids at the carboxy-terminus of the protein. The beta isoform is constitutively expressed through development, whereas the alpha isoform is primarily found in adult muscle. Wu et al. (1994) cloned the human TNTF beta isoform cDNA from a library made from 18-week human fetal skeletal muscle, using a portion of the rabbit TnTf cDNA as a probe. The human cDNAs were derived from a single-copy gene which is expressed primarily in fetal skeletal muscle. The 259-amino acid predicted protein has a hydrophilic hydropathy plot consisting mostly of alpha helical sequence. Wu et al. (1994) observed that the human and rat proteins are approximately 93% identical.
Stefancsik et al. (2003) determined that the TNNT3 gene spans approximately 19 kb and contains 19 exons, including 2 exons specific to fetal and/or neonatal TNNT3. The upstream region contains a TATA box, a CAAT box, several potential E boxes, and an MEF2 (see MEF2A; 600660)-binding site, but no CG-rich regions. The TNNT3 gene also contains an intronic LINE1 element, as well as TC and CCA repeats that are unique to human TNNT3.
By analysis of somatic cell hybrids followed by fluorescence in situ hybridization, Mao et al. (1996) mapped the TNNT3 gene to chromosome 11p15.5. Koch et al. (1997) cloned the mouse homolog and mapped it to the distal region of mouse chromosome 7, which shares homology of synteny with human 11p15-q13.
In a woman and her 2 daughters with distal arthrogryposis type 2B2 (618435), Sung et al. (2003) identified a missense mutation (R63H; 600692.0001) in the TNNI3 gene.
In in vitro studies, Robinson et al. (2007) demonstrated that the TNNT3 R63H mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA2B.
In all affected members of a Chinese family segregating DA2B mapped to chromosome 11p15, Zhao et al. (2011) identified heterozygosity for a missense mutation (R63C; 600692.0002) in the TNNT3 gene. The mutation was not found in an unaffected member of the family or in 100 controls. No causative mutations were identified in the TNNI2 gene, which also maps to 11p15.
In affected members of an Indian family segregating DA2B2, Daly et al. (2014) identified a heterozygous missense mutation (R63S; 600692.0003) in the TNNT3 gene, demonstrating that R63 in the TNNT3 gene is a hotspot for mutation.
In a woman with distal arthrogryposis multiplex congenita type 2B2 (DA2B2; 618435) and her 2 affected daughters, Sung et al. (2003) identified a c.188G-A transition (c.188G-A, NM_006757) in exon 9 of the TNNT3 cDNA, resulting in an arg63-to-his (R63H) substitution. The mutation was thought to be disease-causing for several reasons: it was identified in the proband and was also present in all affected family members; it was not found in 488 chromosomes from an ethnically matched control group; it results in the substitution of an amino acid residue that is conserved in all isoforms of troponin T (TnT), implying that this difference is likely to have structural and/or functional consequences; and Varnava et al. (1999) found that substitution of the homologous amino acid residue in the cardiac-specific form of TnT (TNNT2; 191045) causes cardiomyopathy.
Gurnett et al. (2009) identified the R63H mutation as a de novo occurrence in an infant with 4-extremity arthrogryposis but no facial involvement. The authors noted that it is admittedly difficult to diagnose mild forms of facial weakness, particularly in infancy, although they classified the disorder in this child as distal arthrogryposis-1 (108120).
In affected members of a 4-generation Indian family segregating distal arthrogryposis, Daly et al. (2014) identified heterozygosity for the R63H mutation in the TNNT3 gene. The mutation, which was found by exome sequencing, was confirmed by Sanger sequencing. Daly et al. (2014) classified the phenotype in the family as 'DA1 or a milder variant of DA2B.'
In all 5 affected members of a Chinese family segregating (DA2B2; 618435) mapped to chromosome 11p15, Zhao et al. (2011) identified heterozygosity for a missense mutation (R63C; 600692.0002) in the TNNT3 gene. The mutation, which occurred at the same codon previously reported in patients with DA2B2 (600692.0001), was not found in an unaffected member of the family or in 100 controls.
Daly, S. B., Shah, H., O'Sullivan, J., Anderson, B., Bhaskar, S., Williams, S., Al-Sheqaih, N., Bidchol, A. M., Banka, S., Newman, W. G., Girisha, K. M. Exome sequencing identified a dominant TNNT3 mutation in a large family with distal arthrogryposis. Molec. Syndromol. 5: 218-228, 2014. [PubMed: 25337069] [Full Text: https://doi.org/10.1159/000365057]
Gurnett, C. A., Alaee, F., Desruisseau, D., Boehm, S., Dobbs, M. B. Skeletal muscle contractile gene (TNNT3, MYH3, TPM2): mutations not found in vertical talus or clubfoot. Clin. Orthop. Relat. Res. 467: 1195-1200, 2009. [PubMed: 19142688] [Full Text: https://doi.org/10.1007/s11999-008-0694-5]
Koch, A., Juan, T. S.-C., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., McNiece, I. K., Fletcher, F. A. cDNA cloning and chromosomal mapping of mouse fast skeletal muscle troponin T. Mammalian Genome 8: 346-348, 1997. [PubMed: 9107680] [Full Text: https://doi.org/10.1007/s003359900437]
Mao, C., Baumgartner, A. P., Jha, P. K., Huang, T. H.-M., Sarkar, S. Assignment of the human fast skeletal troponin T gene (TNNT3) to chromosome 11p15.5: evidence for the presence of 11pter in a monochromosome 9 somatic cell hybrid in NIGMS mapping panel 2. Genomics 31: 385-388, 1996. [PubMed: 8838323] [Full Text: https://doi.org/10.1006/geno.1996.0064]
Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function. FASEB J. 21: 896-905, 2007. [PubMed: 17194691] [Full Text: https://doi.org/10.1096/fj.06-6899com]
Stefancsik, R., Randall, J. D., Mao, C., Sarkar, S. Structure and sequence of the human fast skeletal troponin T (TNNT3) gene: insight into the evolution of the gene and the origin of the developmentally regulated isoforms. Comp. Funct. Genomics 4: 609-625, 2003. Note: Erratum: Comp. Funct. Genomics 5: 205 only, 2004. [PubMed: 18629027] [Full Text: https://doi.org/10.1002/cfg.343]
Sung, S. S., Brassington, A.-M. E., Krakowiak, P. A., Carey, J. C., Jorde, L. B., Bamshad, M. Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. (Letter) Am. J. Hum. Genet. 73: 212-214, 2003. [PubMed: 12865991] [Full Text: https://doi.org/10.1086/376418]
Varnava, A., Baboonian, C., Davison, F., de Cruz, L., Elliott, P. M., Davies, M. J., McKenna, W. J. A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy. Heart 82: 621-624, 1999. [PubMed: 10525521] [Full Text: https://doi.org/10.1136/hrt.82.5.621]
Wu, Q.-L., Jha, P. K., Raychowdhury, M. K., Du, Y., Leavis, P. C., Sarkar, S. Isolation and characterization of human fast skeletal beta troponin T cDNA: comparative sequence analysis of isoforms and insight into the evolution of members of a multigene family. DNA Cell Biol. 13: 217-233, 1994. [PubMed: 8172653] [Full Text: https://doi.org/10.1089/dna.1994.13.217]
Zhao, N., Jiang, M., Han, W., Bian, C., Li, X., Huang, F., Kong, Q., Li, J. A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus. Europ. J. Med. Genet. 54: 351-353, 2011. [PubMed: 21402185] [Full Text: https://doi.org/10.1016/j.ejmg.2011.03.002]