Alternative titles; symbols
HGNC Approved Gene Symbol: TCAP
SNOMEDCT: 720522001;
Cytogenetic location: 17q12 Genomic coordinates (GRCh38) : 17:39,665,349-39,666,554 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | Cardiomyopathy, hypertrophic, 25 | 607487 | Autosomal dominant | 3 |
| Muscular dystrophy, limb-girdle, autosomal recessive 7 | 601954 | Autosomal recessive | 3 |
TCAP is a sarcomeric protein found exclusively in striated and cardiac muscle, where it localizes to the periphery of Z discs that define the border of the sarcomere and serve as both a structural anchor and a signaling center. TCAP glues 2 parallel titin (TTN; 188840) within the same sarcomere by directly binding to the N-terminal Z1Z2 domain of titin in a palindromic arrangement, which dramatically increases the mechanical resistance ability of titin (summary by Zhang et al., 2009).
By PCR of a human skeletal muscle cDNA library, Valle et al. (1997) cloned TCAP, which they called telethonin. The deduced 197-amino acid protein has a calculated molecular mass of 19 kD. Northern blot analysis of human tissues detected expression in skeletal and heart muscle only, which was confirmed by RT-PCR analysis. Immunofluorescence analysis of human skeletal muscle showed a banded pattern for TCAP that overlapped with myosin (see 160730) and alternated with actin (see 102610).
The TCAP gene contains 2 exons (Moreira et al., 2000).
Valle et al. (1997) mapped the TCAP gene to chromosome 17q12, adjacent to the phenylethanolamine N-methyltransferase gene (PNMT; 171190).
Using x-ray crystallography, Zou et al. (2006) showed how the amino terminus of the longest filament component in the Z disc of muscle, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z disc ligand telethonin. The pseudosymmetric structure of telethonin mediates a unique palindromic arrangement of 2 titin filaments, a type of molecular assembly previously found only in protein-DNA complexes. Zou et al. (2006) confirmed its unique architecture in vivo by protein complementation assays, and in vitro by experiments using fluorescence resonance energy transfer. Zou et al. (2006) proposed a model that provides a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored, and aligned within complex cytoskeletal networks.
Limb-Girdle Muscular Dystrophy, Autosomal Recessive 7
In affected members of 3 families segregating limb-girdle muscular dystrophy-7 (LGMD7, previously symbolized LGMD2G; 601954), Moreira et al. (2000) identified homozygosity or compound heterozygosity for mutations in the TCAP gene (604488.0001; 604488.0002).
Hypertrophic Cardiomyopathy 25
In 2 Japanese probands with hypertrophic cardiomyopathy-25 (CMH25; 607487), Hayashi et al. (2004) identified heterozygosity for 2 different missense mutations in the TCAP gene, T137I (604488.0004) and R153H (604488.0005).
In a patient with CMH who had massive left ventricular hypertrophy, Bos et al. (2006) identified heterozygosity for a missense mutation in the TCAP gene (R70W; 604488.0006).
Associations Pending Confirmation
For discussion of a possible association between variation in the TCAP gene and dilated cardiomyopathy, see 604488.0003.
Zhang et al. (2009) cloned tcap in zebrafish and showed that it is functionally conserved. The Tcap protein appeared in the sarcomeric Z disc, and reduction of Tcap resulted in muscular dystrophy-like phenotypes including deformed muscle structure and impaired swimming ability. A defective interaction between the sarcomere and plasma membrane was detected, which was further underscored by the disrupted development of the T-tubule system. Zebrafish tcap exhibited a variable expression pattern during somitogenesis. The variable expression was inducible by stretch force, and the expression level of Tcap was negatively regulated by integrin-link kinase (ILK; 602366), a protein kinase that is involved in stretch sensing signaling. The authors suggested that the pathogenesis in LGMD2G may be due to a disruption of sarcomere-tubular interaction, but not of sarcomere assembly per se. Zhang et al. (2009) hypothesized that the transcription level of TCAP may be regulated by the stretch force to ensure proper sarcomere-membrane interaction in striated muscle.
Markert et al. (2010) generated knockout mice carrying a null mutation in the Tcap gene and described skeletal muscle function in 4- and 12-month-old affected mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin (MSTN; 601788), showed that deletion of Tcap was accompanied by increased protein levels of myostatin. The Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wildtype controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus or soleus muscles.
Ibrahim et al. (2013) found that, at 3 months of age, T-tubule density appeared normal in isolated Tcap -/- mouse cardiomyocytes, but that there were isolated T-tubule defects and minor changes in calcium handling. By 8 months of age, Tcap -/- cardiomyocytes showed progressive loss of T-tubules, remodeling of the cell surface, and prolonged and dysynchronous calcium transients. Tcap -/- mice were more sensitive than wildtype to chronic mechanical overload due to thoracic aortic constriction, with increased calcium spark frequency, significantly greater loss of T-tubules, and greater deterioration in T-tubule regularity. Ibrahim et al. (2013) concluded that TCAP is a load-dependent regulator of T-tubule structure and function in the heart.
In affected members of 2 families with limb-girdle muscular dystrophy type 2G (LGMDR7; 601954), Moreira et al. (2000) identified homozygosity for a 157C-T transition in exon 2 of the TCAP gene, resulting in a gln53-to-ter (Q53X) substitution. In affected members of another family with LGMDR7, they identified compound heterozygosity for the Q53X mutation and deletion of 2 guanine nucleotides within 4 guanines at the junction of exon 1 and intron 1 (604488.0002) in the TCAP gene.
In a family with limb-girdle muscular dystrophy type 2G (LGMDR7; 601954), Moreira et al. (2000) found that affected members were compound heterozygotes for the Q53X mutation (604488.0001) and a deletion of 2 guanine nucleotides within a 4 guanine run (nucleotides 637-640 in the genomic sequence) at the junction of exon 1 and intron 1.
This variant, formerly titled CARDIOMYOPATHY, DILATED, 1N (CMD1N; see 607487), has been reclassified as a variant of unknown significance because its contribution to the phenotype has not been confirmed.
Knoll et al. (2002) screened the TCAP gene in 380 patients with dilated cardiomyopathy (CMD) and identified an arg87-to-gln (R87Q) substitution in a single patient, a 46-year-old woman with New York Heart Association functional class I heart failure. The mutation was not found in 100 German or 400 Japanese controls. However, no data concerning the patient's family were provided and no functional studies were performed.
In Y2H assays, Hayashi et al. (2004) measured beta-galactosidase activity to qualitatively investigate the strength of protein-protein interactions between TCAP and the other Z-disc components, MLP (CSRP3; 600824), titin (TTN; 188840), and CS-1 (MYOZ2; 605602), and observed significantly impaired interactions with the R87Q mutant compared to wildtype TCAP. A similar result was obtained in a GST pull-down competition assay. The authors noted that because both methods were in vitro qualitative assays and recombinant proteins were used, the alterations in interaction caused by the TCAP mutation might be different in vivo.
In a Japanese mother and son with hypertrophic cardiomyopathy-25 (CMH25; 607487), Hayashi et al. (2004) identified heterozygosity for a C-T transition in the TCAP gene, resulting in a thr137-to-ile (T137I) substitution at a conserved residue. The mutation was not found in 240 Japanese or 70 Korean controls. The mother's father had died suddenly after exercise at 34 years of age. In vitro qualitative functional analysis showed significantly increased interaction with titin (TTN; 188840) and calsarcin-1 (MYOZ2; 605602) with the T137I mutant compared to wildtype TCAP; the phosphorylation status of TCAP did not affect the interaction.
In a Japanese sister and brother with hypertrophic cardiomyopathy-25 (CMH25; 607487), Hayashi et al. (2004) identified heterozygosity for a G-A transition in the TCAP gene, resulting in an arg153-to-his (R153H) substitution at a conserved residue. The mutation was also detected in the brother's 19- and 21-year-old sons, who did not exhibit CMH at the time of examination, but it was not found in 240 Japanese or 70 Korean controls. The affected sister and brother had 2 sibs who had died suddenly after exercise at age 33 and 44 years. In vitro qualitative functional analysis showed significantly increased interaction with titin (TTN; 188840) and calsarcin-1 (MYOZ2; 605602) with the R153H mutant compared to wildtype TCAP; the phosphorylation status of TCAP did not affect the interaction.
In a 65-year-old Caucasian woman who was diagnosed with hypertrophic cardiomyopathy-25 (CMH25; 607487) at 44 years of age, Bos et al. (2006) identified heterozygosity for an arg70-to-trp (R70W) substitution in the TCAP gene that was not found in 100 Caucasian or 100 black controls. The patient had massive hypertrophy, with a maximum left ventricular wall thickness of 46 mm. Family history included CMH but not sudden cardiac death. Reporting on this patient, Theis et al. (2006) observed that she exhibited a sigmoid septal shape.
Bos, J. M., Poley, R. N., Ny, M., Tester, D. J., Xu, X., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. Molec. Genet. Metab. 88: 78-85, 2006. [PubMed: 16352453] [Full Text: https://doi.org/10.1016/j.ymgme.2005.10.008]
Hayashi, T., Arimura, T., Itoh-Satoh, M., Ueda, K., Hohda, S., Inagaki, N., Takahashi, M., Hori, H., Yasunami, M., Nishi, H., Koga, Y., Nakamura, H., and 10 others. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J. Am. Coll. Cardiol. 44: 2192-2201, 2004. [PubMed: 15582318] [Full Text: https://doi.org/10.1016/j.jacc.2004.08.058]
Ibrahim, M., Siedlecka, U., Buyandelger, B., Harada, M., Rao, C., Moshkov, A., Bhargava, A., Schneider, M., Yacoub, M. H., Gorelik, J., Knoll, R., Terracciano, C. M. A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart. Hum. Molec. Genet. 22: 372-383, 2013. [PubMed: 23100327] [Full Text: https://doi.org/10.1093/hmg/dds434]
Knoll, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M.-L., Hayashi, T., Shiga, N., Yasukawa, H., Schaper, W., McKenna, W., Yokoyama, M., and 9 others. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111: 943-955, 2002. [PubMed: 12507422] [Full Text: https://doi.org/10.1016/s0092-8674(02)01226-6]
Markert, C. D., Meaney, M. P., Voelker, K. A., Grange, R. W., Dalley, H. W., Cann, J. K., Ahmed, M., Bishwokarma, B., Walker, S. J., Yu, S. X., Brown, M., Lawlor, M. W., Beggs, A. H., Childers, M. K. Functional muscle analysis of the Tcap knockout mouse. Hum. Molec. Genet. 19: 2268-2283, 2010. [PubMed: 20233748] [Full Text: https://doi.org/10.1093/hmg/ddq105]
Moreira, E. S., Wiltshire, T. J., Faulkner, G., Nilforoushan, A., Vainzof, M., Suzuki, O. T., Valle, G., Reeves, R., Zatz, M., Passos-Bueno, M. R., Jenne, D. E. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nature Genet. 24: 163-166, 2000. [PubMed: 10655062] [Full Text: https://doi.org/10.1038/72822]
Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy. Biochem. Biophys. Res. Commun. 351: 896-902, 2006. [PubMed: 17097056] [Full Text: https://doi.org/10.1016/j.bbrc.2006.10.119]
Valle, G., Faulkner, G., De Antoni, A., Pacchioni, B., Pallavicini, A., Pandolfo, D., Tiso, N., Toppo, S., Trevisan, S., Lanfranchi, G. Telethonin, a novel sarcomeric protein of heart and skeletal muscle. FEBS Lett. 415: 163-168, 1997. [PubMed: 9350988] [Full Text: https://doi.org/10.1016/s0014-5793(97)01108-3]
Zhang, R., Yang, J., Zhu, J., Xu, X. Depletion of zebrafish Tcap leads to muscular dystrophy via disrupting sarcomere-membrane interaction, not sarcomere assembly. Hum. Molec. Genet. 18: 4130-4140, 2009. [PubMed: 19679566] [Full Text: https://doi.org/10.1093/hmg/ddp362]
Zou, P., Pinotsis, N., Lange, S., Song, Y.-H., Popov, A., Mavridis, I., Mayans, O. M., Gautel, M., Wilmanns, M. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439: 229-233, 2006. [PubMed: 16407954] [Full Text: https://doi.org/10.1038/nature04343]