Alternative titles; symbols
HGNC Approved Gene Symbol: TNNC2
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:45,823,214-45,833,306 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Congenital myopathy 15 | 620161 | Autosomal dominant | 3 |
The troponin complex, a key regulator of sarcomeric muscle contraction, is composed of 3 subunits: troponin C, troponin I, and troponin T. The troponin C protein is the calcium-binding subunit of the troponin complex (summary by Gahlmann and Kedes, 1990).
Gahlmann et al. (1988) showed that there are only 2 troponin C genes in the human genome, one encoding fast skeletal troponin C and the other encoding slow/cardiac troponin C (TNNC1; 191040).
Gahlmann and Kedes (1990) described the structure and sequence of the gene for fast-twitch troponin C. The gene contains 6 exons.
By PCR-based analysis of a monochromosomal hybrid panel followed by analysis of the Genebridge 4 radiation hybrid panel, Townsend et al. (1997) mapped the TNNC2 gene to chromosome 20. Tiso et al. (1997) independently mapped the TNNC2 gene to 20q12-q13.11 using PCR of radiation hybrids.
Stumpf (2022) mapped the TNNC2 gene to chromosome 20q13.12 based on an alignment of the TNNC2 sequence (GenBank BC005323) with the genomic sequence (GRCh38).
In 4 patients from 2 unrelated families with congenital myopathy-15 (CMYP15; 620161), van de Locht et al. (2021) identified 2 different heterozygous missense mutations in the TNNC2 gene (D34Y, 191039.0001 and M79I, 191039.0002). The mutations, which were found by exome sequencing, were absent from the gnomAD database. The mutation was inherited in an autosomal dominant pattern in 1 family and occurred de novo in the proband from the second family. In vitro studies of fast-twitch myofibers derived from patient skeletal muscle showed a markedly reduced force response of the sarcomeres to calcium, consistent with reduced calcium sensitivity. Of note, the maximal force-generating capacity of the sarcomeres in both fast-twitch and slow-twitch myofibers was similar to controls. Expression of the mutations in control myofibers resulted in decreased calcium force sensitivity, and expression of wildtype TNNC2 in patient myofibers restored the calcium force sensitivity to control levels. Both mutations had a dominant effect when coexpressed with wildtype TNNC2, suggesting that haploinsufficiency was an unlikely pathogenetic mechanism. Exposure of patient fast-twitch myofibers to the pharmaceutical fast skeletal muscle activator tirasemtiv restored the calcium sensitivity of force to control levels in vitro.
In 3 affected members of a 3-generation family (family 1) with congenital myopathy-15 (CMYP15; 620161), van de Locht et al. (2021) identified a heterozygous c.100G-T transversion in the TNNC2 gene, resulting in an asp34-to-tyr (D34Y) substitution at a highly conserved residue in the calcium-binding site I domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. Molecular modeling suggested that the mutation may impact calcium binding to the first EF hand and disrupt interactions with other components of the troponin complex. In vitro studies of fast-twitch myofibers derived from patient skeletal muscle showed a markedly reduced force response of the sarcomeres to calcium, consistent with reduced calcium sensitivity.
In a 19-year-old girl (family 2) with congenital myopathy-15 (CMYP15; 620161), van de Locht et al. (2021) identified a de novo heterozygous c.237G-C transversion in the TNNC2 gene, resulting in a met79-to-ile (M79I) substitution at a highly conserved residue in an alpha-helix next to calcium-binding site II. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Molecular modeling suggested that the mutation may disrupt calcium binding and interactions with other components of the troponin complex. In vitro studies of fast-twitch myofibers derived from patient skeletal muscle showed a markedly reduced force response of the sarcomeres to calcium, consistent with reduced calcium sensitivity.
Gahlmann, R., Kedes, L. Cloning, structural analysis, and expression of the human fast twitch skeletal muscle troponin C gene. J. Biol. Chem. 265: 12520-12528, 1990. [PubMed: 2373703]
Gahlmann, R., Wade, R., Gunning, P., Kedes, L. Differential expression of slow and fast skeletal muscle troponin C: slow skeletal muscle troponin C is expressed in human fibroblasts. J. Molec. Biol. 201: 379-391, 1988. [PubMed: 3166492] [Full Text: https://doi.org/10.1016/0022-2836(88)90145-3]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/21/2022.
Tiso, N., Rampoldi, L., Pallavicini, A., Zimbello, R., Pandolfo, D., Valle, G., Lanfranchi, G., Danieli, G. A. Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast. Biochem. Biophys. Res. Commun. 230: 347-350, 1997. [PubMed: 9016781] [Full Text: https://doi.org/10.1006/bbrc.1996.5958]
Townsend, P. J., Yacoub, M. H., Barton, P. J. R. Assignment of the human fast skeletal muscle troponin C gene (TNNC2) between D20S721 and GCT10F11 on chromosome 20 by somatic cell hybrid analysis. Ann. Hum. Genet. 61: 457-459, 1997. [PubMed: 9459007] [Full Text: https://doi.org/10.1046/j.1469-1809.1997.6150457.x]
van de Locht, M., Donkervoort, S., de Winter, J. M., Conijn, S., Begthel, L., Kusters, B., Mohassel, P., Hu, Y., Medne, L., Quinn, C., Moore, S. A., Foley, A. R., and 13 others. Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium. J. Clin. Invest. 131: e145700, 2021. [PubMed: 33755597] [Full Text: https://doi.org/10.1172/JCI145700]