The Novel Sarcomeric Protein Telethonin Exhibits Developmental and Functional Regulation

doi:10.1006/bbrc.1999.0531

Biochemical and Biophysical Research Communications

Volume 257, Issue 3, 21 April 1999, Pages 699-703

https://doi.org/10.1006/bbrc.1999.0531 Get rights and content

Abstract

We have isolated a cDNA clone from a mouse skeletal muscle library which is preferentially expressed in striated muscle and exhibits a high homology to human telethonin, a sarcomeric protein. The mouse telethonin transcript is developmentally regulated in both cardiac and skeletal musclein vivoand is down-regulated in response to denervation. In the C2C12 muscle cell-line the mouse telethonin transcript exhibited a pattern of accumulation similar to that observed for a contractile protein and suggests a role in myofibrillar assembly.

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Cited by (33)

Cell states beyond transcriptomics: Integrating structural organization and gene expression in hiPSC-derived cardiomyocytes
2021, Cell Systems
Citation Excerpt :
To do this, we performed RNA FISH for 16 gene transcripts as multiplexed pairs in 11,135 alpha-actinin-2-mEGFP expressing cardiomyocytes at D18 and D32 (Figures S5A–S5C; Table S3). Five of these genes were chosen because of their association with known sarcomere biology at a structural, regulatory, or functional level and included MYL7, ATP2A2, TCAP, NKX2.5, and BAG3 (Judge et al., 2017; Kasahara et al., 2003; Kubalak et al., 1994; MacLennan et al., 1985; Mason et al., 1999; Sacchetto et al., 2020). The remaining 11 genes were chosen based on results in a complementary transcriptomic study (Grancharova et al., 2021), where groups of genes were identified for their ability to correctly assign cardiomyocytes to a selected time point, which included MYH7, MYH6, COL2A1, H19, VCAN, CNTN5, MEF2C, PLN, PRSS35, BMPER, and housekeeping gene HPRT1 (Bargehr et al., 2019; Bertero et al., 2019; Friedman et al., 2018; Palpant et al., 2017) (Figures 6B–6E and S5A–S5C).
Although some cell types may be defined anatomically or by physiological function, a rigorous definition of cell state remains elusive. Here, we develop a quantitative, imaging-based platform for the systematic and automated classification of subcellular organization in single cells. We use this platform to quantify subcellular organization and gene expression in >30,000 individual human induced pluripotent stem cell-derived cardiomyocytes, producing a publicly available dataset that describes the population distributions of local and global sarcomere organization, mRNA abundance, and correlations between these traits. While the mRNA abundance of some phenotypically important genes correlates with subcellular organization (e.g., the beta-myosin heavy chain, MYH7), these two cellular metrics are heterogeneous and often uncorrelated, which suggests that gene expression alone is not sufficient to classify cell states. Instead, we posit that cell state should be defined by observing full distributions of quantitative, multidimensional traits in single cells that also account for space, time, and function.
Limb girdle muscular dystrophy 2G in a religious minority of Bulgarian Muslims homozygous for the c.75G>A, p.Trp25X mutation
2018, Neuromuscular Disorders
Citation Excerpt :
Although rare the earlier onset of TCAP mutations is not unusual since there are previous reports of a LGMD2G cases with initial symptoms in the first decade [3,16,17] and patients with features consistent with congenital muscular dystrophy [7,8]. Muscle involvement in our patients followed the previously reported pattern [1–5], with initial and severe proximal weakness in lower limbs, accompanied or followed by weakness of anterior tibialis muscles, and later involvement of the upper limb muscles. Calf hypertrophy, scapular winging, and joint contractures were observed in some patients.
Mutations in TCAP gene cause autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G), congenital muscular dystrophy and autosomal dominant dilated and hypertrophic cardiomyopathy. We studied 18 affected individuals from 12 pedigrees, belonging to a Bulgarian Muslim minority from the South-West of Bulgaria, homozygous for the c.75G>A, p.Trp25X mutation in TCAP gene. The heterozygous carrier rate of p.Trp25X among 100 newborns in this region was found to be 2%. The clinical features in the Bulgarian TCAP group include disease onset in the first to the third decade of life, proximal muscle weakness in the lower limbs, followed or accompanied by difficulties in ankle dorsiflexion and involvement of the proximal muscles of the upper limbs 5–9 years after the disease onset. Asymmetry between left and right was present in more than 20% of the affected. Respiratory and cardiac functions were not affected. On the MRI the muscles of the posterior pelvic area, thigh and anterior leg were predominantly affected, while sartorius, gracilis and biceps femoris muscles remained relatively spared.
In conclusion, LGMD2G appears to be a common form among Bulgarian Muslims. Homozygosity for c.75G>A, p.Trp25X is associated with a homogeneous clinical presentation, but the clinical course and severity of the disease show inter- and intra-familial variation.
Comparative proteomic analysis of hearts of adult SCNT Bama miniature pigs (Sus scrofa)
2014, Theriogenology
Citation Excerpt :
As a 19-kDa sarcomeric protein localized in the Z disc, telethonin (also known as TCAP, spot 2835) plays a pivotal role in cardiomyocyte structure and function, and exclusively expresses in adult skeletal and cardiac muscle [31–33]. It has been shown that telethonin can bind titin and other sarcomeric proteins at the Z disc, and plays an important role in sarcomeric assembly, sarcomere–membrane interactions and stretch sensing [32–34]. Gregorio, et al. [35] thought that the overexpression of telethonin and Z1Z2 (two Ig domains from the N terminus of titin) might disrupt the association of titin filaments and the ultrastructure of the Z disc.
This study aims to determine the effects of SCNT on cardiac development of SCNT pigs through proteomic methods. Heart proteins from three adult SCNTs and two normal reproductive Bama miniature pigs were extracted, separated, and identified via comparative proteomic methods, including two-dimensional gel electrophoresis, mass spectrometry, and Western blot. Eleven differentially expressed spots were identified as differentially expressed proteins, of which five spots were upregulated proteins such as cardiac myosin heavy chain, cathepsin D, and heat shock protein beta-1 (HSP27). By contrast, six spots were downregulated proteins such as alpha skeletal muscle and actin. The results also demonstrated that nuclear transfer might result in abnormal expression of some important proteins in hearts from SCNT pigs, and affect the cardiac development in SCNT pigs' survival.
Molecular characterization, transcriptional regulation and association analysis with carcass traits of porcine TCAP gene
2014, Gene
Citation Excerpt :
We found that the transcriptional activities of all constructions were higher in C2C12 cells than in PK15 cells, and the activities in myotubes were significantly higher than in myoblasts. These data are generally in agreement with the previous report that the expression of mouse TCAP gene was greatly upregulated during the differentiation of C2C12 myoblast cells (Mason et al., 1999). The results show that the porcine TCAP promoter is a muscle-specific promoter and it may have a close relationship with cell proliferation and differentiation.
TCAP (also known as titin-cap or telethonin) is one of the titin interacting Z-disk proteins involved in the regulation and development of normal sarcomeric structure. In this study, we cloned the cDNA and promoter sequences of porcine TCAP gene, which contained a 504 bp full-length coding region. Quantitative real-time PCR (qRT-PCR) analyses showed that porcine TCAP was highly expressed in the skeletal muscle, heart, and kidney. During postnatal muscle development, TCAP expression was down-regulated from 30 days to 120 days in Large White and Meishan pigs. One single nucleotide polymorphism c.334G>A in exon 2 of the TCAP gene was identified and detected by allele-specific primer-polymerase chain reaction (ASP-PCR). Association analysis revealed that the polymorphism had significant associations (P < 0.05 and P < 0.01) with some carcass traits. Analysis of the porcine TCAP promoter in different cell lines demonstrated that it is a muscle-specific promoter. In addition, we found that the porcine TCAP promoter can be activated by MyoD, MyoG and MEF2 in myotubes, which indicated that TCAP may play a role in the regulation of porcine skeletal muscle development. These findings provide useful information for the further investigation of the function of TCAP in porcine skeletal muscle.
Telethonin-deficiency initially presenting as a congenital muscular dystrophy
2011, Neuromuscular Disorders
Congenital muscular dystrophies are defined by congenital or infantile onset of muscle weakness; while 12 culprit genes have been identified, many cases remain molecularly uncharacterized. On the other hand, mutations in the telethonin gene (TCAP) have been associated with a rare form of recessive limb girdle muscular dystrophy, usually presenting in the second decade.
So far, three different mutations in telethonin have been reported in patients suffering from limb muscular dystrophy type 2G. We have identified a novel telethonin mutation in a child presenting with mildly delayed motor development and muscle weakness from infancy, clinically improving over the first decade, indicative of a CMD. Muscle biopsy showed a dystrophic process, with preserved laminin α2, collagen VI, and α-dystroglycan, but absent telethonin immunolabeling. Sequence analysis of TCAP showed a novel non-sense p.Gln58X (c.172C > T) homozygous mutation. Our observation indicates that telethonin deficiency may present in infancy with clinical features overlapping with mild forms of α-dystroglycanopathy. Therefore telethonin analysis should be performed in patients suffering from congenital muscular dystrophy of unknown cause.
Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient
2008, Neuromuscular Disorders
A 27-year-old woman of Moldavian origin presented at the age of 15 with progressive proximal limb weakness and painful cramps in her calf muscles. Clinical examination revealed prominent muscle weakness in proximal muscles of the lower extremities and distal anterior compartment of legs, and mild weakness in shoulder girdle muscles. In addition, she had marked calf hypertrophy, muscle atrophy involving the anterior and posterior compartments of the thighs, and the distal anterior compartment of legs, as well as mild scapular winging and hyperlordosis. A muscle biopsy taken from the biceps brachii showed mild dystrophic changes, absent vacuoles, and abundant lobulated fibers. Immunofluorescence and Western blot assays demonstrated complete telethonin deficiency. Molecular analysis revealed a homozygous Trp25X mutation in the telethonin (TCAP) gene resulting in termination of transcription at an early point. Four families from Brazil with telethonin deficiency have previously been reported and classified as LGMD2G, but the actual frequency of this disease is unknown. With this current identification of a case outside the Brazilian population, telethonin mutation-associated LGMD should be considered worldwide.

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Regular ArticleThe Novel Sarcomeric Protein Telethonin Exhibits Developmental and Functional Regulation

Abstract

FEBS Letts.

Biochem. Biophys. Res. Commun.

Gene

Biochem. Biophys. Res. Comm.

FEBS Letts.

Physiological Rev.

Regular Article
The Novel Sarcomeric Protein Telethonin Exhibits Developmental and Functional Regulation