Alternative titles; symbols
HGNC Approved Gene Symbol: TRDN
Cytogenetic location: 6q22.31 Genomic coordinates (GRCh38): 6:123,216,339-123,636,950 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.31 | Cardiac arrhythmia syndrome, with or without skeletal muscle weakness | 615441 | Autosomal recessive | 3 |
The triadin gene is alternatively spliced to produce several isoforms that are differentially expressed in skeletal and cardiac muscle. Some isoforms localize to longitudinal regions of the sarcoplasmic reticulum (SR), and others localize to triad junctions, where T-tubules and SR terminal cisternae are in close contact. Triadin isoforms localized to triad junctions appear to have a role in excitation-contraction coupling (summary by Oddoux et al., 2009).
The dihydropyridine-sensitive calcium channels (see CACNA2; 114204) and ryanodine-sensitive calcium channels (RYR1; 180901) of skeletal muscle play key roles in the generation of calcium transients during excitation/contraction coupling. The coupling of the signal for calcium release between these proteins occurs at highly specialized triadic junctions that separate the T-tubule membrane and the terminal cisternae of the SR. Triadin, a protein found in rabbit triadic junctions, is intrinsic to the terminal cisternae and is closely associated with RYR1. By RT-PCR of human skeletal muscle RNA with primers based on the sequence of a rabbit triadin cDNA, Taske et al. (1995) isolated cDNAs encoding human triadin. The predicted 729-amino acid human protein shares 95% identity with rabbit triadin. Like the rabbit protein, human triadin contains a small cytoplasmic domain and a single transmembrane domain. Human triadin has a calculated pI of 9.3 and molecular mass of 82 kD. However, on Western blots, its apparent molecular mass is 117 kD. Taske et al. (1995) suggested that triadin has reduced mobility because it is a highly charged protein. Northern blot analysis revealed that triadin is expressed as a 4.8-kb mRNA in human skeletal muscle.
By PCR and 3-prime and 5-prime RACE, Thevenon et al. (2003) cloned 2 triadin isoforms from a skeletal muscle cDNA library. The longer isoform, TRISK95, contains 729 amino acids and has a calculated molecular mass of about 95 kD. The shorter isoform, TRISK51, results from the use of an internal splice site within exon 21. It contains 461 amino acids and has a calculated molecular mass of about 51 kD. The TRISK51 and TRISK95 transcripts are both about 4.5 kb. In rat skeletal muscle, expression of Trisk95 and Trisk51 was roughly equivalent. However, RT-PCR and Western blot analysis of human deltoid and quadriceps muscle indicated that TRISK51 was expressed at high levels, while TRISK95 was expressed at low levels. Immunologic labeling of longitudinal sections of skeletal muscle revealed signal localized to the junctional triad.
Hong et al. (2001) cloned several isoforms of mouse Trdn from skeletal and cardiac muscle. All 3 isoforms have identical N-terminal sequences of 262 amino acids and distinct C-terminal sequences. The isoforms expressed in cardiac muscle were about 1.3, 4.3, and 5.0 kb and corresponded to deglycosylated proteins of 35, 35.5, and 40 kD, respectively. In skeletal muscle, the transcripts sizes were 5.0, 5.5, and 7.0 kb.
Shen et al. (2007) stated that triadin isoforms of 95 and 60 kD are expressed in triad junctions of mouse skeletal muscle, that isoforms of 32 and 40 kD are expressed in triad junctions of heart, and that nontriad isoforms of 49 and 32 kD are expressed in skeletal muscle.
Thevenon et al. (2003) determined that the TRDN gene contains 41 exons and spans 420 kb. Exon 1 contains the initiation codon, and exon 41 contains the stop codon and 1.3 kb of 3-prime untranslated sequence.
By fluorescence in situ hybridization, Taske et al. (1995) mapped the triadin gene to 6q22-q23.
Using the alpha-myosin heavy chain (160710) promoter to drive protein expression, Kirchhefer et al. (2001) developed transgenic mice overexpressing Trdn1, the dominant cardiac isoform of mouse triadin, in the atrium and ventricle. Expression was elevated 5-fold and was accompanied by cardiac hypertrophy. The levels of 2 other junctional SR proteins, RYR2 (180902) and junctin (ASPH; 600582), were reduced by 55% and 73%, respectively. The levels of the junctional SR Ca(2+)-binding protein, calsequestrin (114251), and the free SR Ca(2+)-handling proteins, phospholamban (172405) and Serca2a (180740), were unchanged. The contractile phenotype of hearts from triadin-overexpressing mice included impaired relaxation, blunted contractility with increased pressure loading, and frequency-dependent changes in myocyte shortening. Kirchhefer et al. (2001) concluded that Trdn1 plays an active role in Ca(2+) release, beyond its previously proposed structural role of anchoring calsequestrin to RYR2.
From a cohort of 97 patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; see 604772) in whom mutations in the RYR2 (180902) and CASQ2 (114251) genes had been excluded, Roux-Buisson et al. (2012) identified 2 probands with biallelic mutations in the TRDN gene. Both patients had onset of severe cardiac arrhythmias in infancy or early childhood, and 1 also had skeletal muscle weakness (cardiac arrhythmia syndrome with or without skeletal muscle weakness, CARDAR; 615441). One proband was a 2-year-old boy from the French West Indies who was homozygous for a frameshift mutation (603283.0001), and the other was a 26-year-old French man who was compound heterozygous for a missense (T59R; 603283.0002) and a nonsense (Q205X; 603283.0003) mutation. The authors noted that the 3 TRDN mutations were located in a region of the gene common to all triadin isoforms, including skeletal muscle isoforms.
In a 10-year-old girl (family 1) with severe cardiac arrhythmias and a prolonged QT interval, who was negative for mutation in known long QT syndrome (LQTS; see 192500)-associated genes, Altmann et al. (2015) identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (603283.0001). Subsequent analysis of the TRDN gene in 33 unrelated patients with LQTS revealed 4 more children with mutations in TRDN: 3 were homozygous for a 5-bp deletion (603283.0004) and 1 was compound heterozygous for the 5-bp deletion and a splicing mutation (603283.0005). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases.
In 2 sisters from a French family with CPVT, Rooryck et al. (2015) identified compound heterozygosity for 2 previously reported mutations in the TRDN gene: Q205X (603283.0003) and a splicing mutation (603283.0005). Their unaffected parents were each heterozygous for 1 of the mutations; their asymptomatic 3-year-old sister was also compound heterozygous for the variants.
In a brother and sister with cardiac arrest at age 2 years and possible prolongation of the QT interval on ECG, Walsh et al. (2016) identified compound heterozygosity for the previously reported 4-bp deletion (603283.0001) and a nonsense mutation in the TRDN gene (E168X; 603283.0006).
O'Callaghan et al. (2018) studied an Omani male infant who experienced cardiac arrest at age 16 months and showed prolonged QTc and T-wave inversion in the anterior precordial leads on ECG. Subsequent ECGs documented torsades de pointes and ventricular fibrillation. Next-generation sequencing targeting 54 cardiac arrhythmia-associated genes revealed mutations in 3 genes: an apparently homozygous deletion of exon 2 of the TRDN gene; a previously reported missense mutation in the KCNE2 gene (I57T; 603796.0003), associated with long QT syndrome (LQT6; 613693); and a E3783Q substitution in the RYR2 gene of uncertain significance.
In an Afghan family in which 2 sibs had died suddenly and a third child was resuscitated from cardiac arrest, Rossi et al. (2020) identified homozygosity for a missense mutation in the TRDN gene (L56P; 603283.0007) that segregated with disease in the family. Functional analysis suggested that the L56P variant may trigger arrhythmias by altering calcium homeostasis.
Shen et al. (2007) found that mice with complete knockout of triadin expression appeared normal in their survival, fertility, and movements. Western blot analysis of SR proteins in Trdn -/- skeletal muscle showed downregulation of junctophilin-1 (JPH1; 605266), junctin (ASPH; 600582), and calsequestrin (see 114250). Some calsequestrin was also detected in tubes of the longitudinal SR in Trdn -/- muscle. Expression of junctin and Ryr1 (180901) was differentially affected in slow and fast Trdn -/- muscle. Trdn -/- muscle showed reduced amplitude of calcium transients and increased myoplasmic resting free Ca(2+), but it did not show contractile dysfunction. Minor disorganization of triadic junctions was observed in fast-twitch, but not slow-twitch, Trdn -/- muscle fibers.
The calcium release unit is a multiprotein complex whose principal components include the L-type calcium channel Cav1.2 (CACNA1C; 114205) and Ryr2 (180902). Chopra et al. (2009) found that homozygous deletion of Trdn in mice resulted in defective excitation-contraction coupling in heart, concomitant with significant changes in the structure and protein composition of the cardiac calcium release unit. Electron microscopy of Trdn -/- hearts showed fragmentation and an overall 50% reduction in the contacts between cardiac junctional SR and T-tubules, with reduced colocalization of Cav1.2 with Ryr2. Calcium release unit function was impaired in Trdn -/- myocytes, with reduced SR calcium release and impaired negative feedback of SR calcium release in response to Cav1.2 calcium currents. Beta-adrenergic receptor (see 109630) stimulation caused ventricular arrhythmias in Trdn -/- mice and spontaneous SR calcium release in isolated Trdn -/- myocytes, likely due to uninhibited calcium influx.
Independently, Oddoux et al. (2009) found that deletion of Trdn expression in mice altered the composition of the calcium release complex in fast and slow skeletal muscle, caused abnormal orientation of triads with loss of associated mitochondria, and reduced SR terminal cisternae volume and calcium content. Trdn -/- mice showed reduced strength, and both fast- and slow-twitch muscle from Trdn -/- mice showed reduced twitch and tetanic forces, but improved resistance to fatigue.
In a 2-year-old boy with cardiac arrhythmia syndrome (CARDAR; 615441) who died after cardiac arrest due to catecholaminergic polymorphic ventricular tachycardia (CPVT), Roux-Buisson et al. (2012) identified homozygosity for a 4-bp deletion (c.53_56delACAG) in exon 2 of the TRDN gene, resulting in a frameshift predicted to result in a premature termination codon (Asp18AlafsTer13) before the transmembrane helix in the cardiac isoform of triadin (TRISK32). The mutation was present in heterozygosity in the proband's unaffected parents and older brother. Haplotype analysis in the family suggested a remote common ancestor. Roux-Buisson et al. (2012) remarked that the young age of the patient precluded detection of skeletal muscle weakness.
In a 10-year-old black girl (family 1) with CARDAR with severe cardiac arrhythmias and a prolonged QT interval, Altmann et al. (2015) identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (c.53_56delACAG, NM_001256021.1) for which her unaffected parents were heterozygous. The authors noted that the variant was not found in the 1000 Genomes Project database or in white exomes in the NHLBI GO ESP database, but was present in 1 of 1,861 black exomes in GO ESP, and was also present in the ExAC database at an overall minor allele frequency of 0.01%, and in black exomes at 0.14%. Skeletal muscle weakness was noted to be absent.
In a brother and sister with CARDAR who both experienced cardiac arrest at 2 years of age and showed possible prolongation of the QT interval, Walsh et al. (2016) identified compound heterozygosity for the 4-bp deletion in the TRDN gene and a c.502G-T transversion, resulting in a glu168-to-ter (E168X; 603283.0006) substitution. Their unaffected parents were each heterozygous for 1 of the mutations. Walsh et al. (2016) attributed residual generalized weakness in the sister to the mutation, and noted that the gross motor development of the brother was slightly delayed compared to that of his half-sibs.
In 26-year-old dizygotic twin brothers with cardiac arrhythmia syndrome (CARDAR; 615441), who from infancy experienced exercise-induced syncope due to catecholaminergic polymorphic ventricular tachycardia, Roux-Buisson et al. (2012) identified compound heterozygosity for 2 mutations in the TRDN gene: a c.176C-G transversion in exon 2, resulting in a thr59-to-arg (T59R) substitution at a well-conserved residue within the transmembrane domain of the cardiac isoform of triadin (TRISK32), and a c.613C-T transition in exon 8, resulting in a gln205-to-ter substitution (Q205X; 603283.0003) before the KEKE region. One of the brothers also had proximal muscle weakness. Unaffected family members who were tested carried 1 or none of the variants. Analysis of TRISK32 in COS-7 cells showed that whereas wildtype TRISK32 was localized in the plasma membrane of 83% of cells and in the endoplasmic reticulum (ER) in 17%, T59R mutant TRISK32 was retained in the ER in 100% of cells and was prone to degradation, most likely via the proteasomal pathway. RT-PCR and Western blot analysis of cardiomyocytes from TRDN-knockout mice after viral transduction of the T59R-TRDN mutant demonstrated that although the mutant transcript is expressed, the protein is absent.
For discussion of the c.613C-T transition in the TRDN gene, resulting in a gln205-to-ter (Q205X) substitution, that was found in compound heterozygous state in twin brothers with cardiac arrhythmia syndrome with or without skeletal muscle weakness (CARDAR; 615441) by Roux-Buisson et al. (2012), see 603283.0002.
In 2 sisters (II.1 and II.2) from a French family with CARDAR manifest as catecholaminergic polymorphic ventricular tachycardia (CPVT), who did not have muscle weakness, Rooryck et al. (2015) identified compound heterozygosity for the Q205X mutation in the TRDN gene, and a splicing mutation (c.22+29A-G; 603283.0005). Their unaffected parents were each heterozygous for 1 of the mutations, which were both found at low minor allele frequency in the ExAC database (0.00003244 and 0.000008339, respectively). Their asymptomatic 3-year-old sister (II.3) was also compound heterozygous for the TRDN mutations. In vitro minigene assay demonstrated that the splicing mutation results in an elongation of exon 1 by 29 bases, causing a frameshift and premature termination codon. (In their article, Rooryck et al. (2015) correctly referred to the mutation as Q205X but incorrectly as Glu205Ter.)
In 3 unrelated children (families 2, 3, and 4) with cardiac arrhythmia syndrome (CARDAR; 615441) who experienced syncope or cardiac arrest before 3 years of age and had long QT intervals on electrocardiography, Altmann et al. (2015) identified homozygosity for a 5-bp deletion (c.572_576delTAAGA, NM_001256021.1) in the TRDN gene, resulting in an immediate stop codon (Lys147fsTer0). One child (family 2) also exhibited mild proximal muscle weakness, and another (family 4) showed polymorphic and bidirectional ventricular tachycardia on electrocardiography, in addition to transient QT prolongation. A fourth child (family 5), who experienced cardiac arrest at age 20 months and exhibited mild to moderate skeletal muscle weakness and decreased muscle tone at age 4 years, was compound heterozygous for the 5-bp deletion and a splicing mutation (c.22+29A-G; 603283.0005). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases.
For discussion of the c.22+29A-G transition (c.22+29A-G, NM_001256021.1) in intron 1 of the TRDN gene that was found in compound heterozygous state in a 4-year-old boy (family 5) with cardiac arrhythmia syndrome and skeletal muscle weakness (CARDAR; 615441) by Altmann et al. (2015), see 603283.0004. For discussion of the same splicing mutation found in compound heterozygous state in 3 French sisters with CARDAR without skeletal muscle weakness by Rooryck et al. (2015), see 603283.0003.
For discussion of the c.502G-T transversion in the TRDN gene, resulting in a glu168-to-ter (E168X) substitution, that was found in compound heterozygous state in a brother and sister with cardiac arrhythmia syndrome (CARDAR; 615441) by Walsh et al. (2016), see 603283.0001.
In an Afghan family with cardiac arrhythmia syndrome (CARDAR; 615441) in which 2 sibs had died suddenly at ages 2 years and 3 years, and a third child was resuscitated from cardiac arrest at age 14 months and showed prolongation of the QT interval on electrocardiography, Rossi et al. (2020) identified homozygosity for a c.167T-C transition (c.167T-C, NM_006073.3) in the TRDN gene, resulting in a leu56-to-pro (L56P) substitution at a highly conserved residue within the transmembrane helix domain. The variant segregated with disease in the family and was not found in the 1000 Genomes Project or gnomAD databases. Functional analysis in transfected HeLa cells showed that the mobile fraction with the L56P variant was significantly higher than that with the wildtype protein, suggesting that the L56P mutation increases triadin mobility in the endoplasmic reticulum membrane. In addition, HEK293T cells expressing RYR2 (180902) channels showed a peak magnitude of caffeine-stimulated calcium release that was significantly reduced with the L56P mutant compared to wildtype TRDN. Rossi et al. (2020) noted that while the index case in this family did not show signs of myopathy, this could be due to his very young age, and could not exclude future muscular involvement.
Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J. Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome. Circulation 131: 2051-2060, 2015. [PubMed: 25922419] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.115.015397]
Chopra, N., Yang, T., Asghari, P., Moore, E. D., Huke, S., Akin, B., Cattolica, R. A., Perez, C. F., Hlaing, T., Knollmann-Ritschel, B. E. C., Jones, L. R., Pessah, I. N., Allen, P. D., Franzini-Armstrong, C., Knollmann, B. C. Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias. Proc. Nat. Acad. Sci. 106: 7636-7641, 2009. [PubMed: 19383796] [Full Text: https://doi.org/10.1073/pnas.0902919106]
Hong, C.-S., Ji, J.-H., Kim, J. P., Jung, D. H., Kim, D. H. Molecular cloning and characterization of mouse cardiac triadin isoforms. Gene 278: 193-199, 2001. [PubMed: 11707337] [Full Text: https://doi.org/10.1016/s0378-1119(01)00718-1]
Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., Schmitz, W., Jones, L. R. Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1. J. Biol. Chem. 276: 4142-4149, 2001. [PubMed: 11069905] [Full Text: https://doi.org/10.1074/jbc.M006443200]
O'Callaghan, B. M., Hancox, J. C., Stuart, A. G., Armstrong, C., Williams, M. M., Hills, A., Pearce, H., Dent, C. L., Gable, M., Walsh, M. A. A unique triadin exon deletion causing a null phenotype. HeartRhythm Case Rep. 4: 514-518, 2018. [PubMed: 30479949] [Full Text: https://doi.org/10.1016/j.hrcr.2018.07.014]
Oddoux, S., Brocard, J., Schweitzer, A., Szentesi, P., Giannesini, B., Brocard, J., Faure, J., Pernet-Gallay, K., Bendahan, D., Lunardi, J., Csernoch, L., Marty, I. Triadin deletion induces impaired skeletal muscle function. J. Biol. Chem. 284: 34918-34929, 2009. [PubMed: 19843516] [Full Text: https://doi.org/10.1074/jbc.M109.022442]
Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B. New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene. J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015. [PubMed: 26200674] [Full Text: https://doi.org/10.1111/jce.12763]
Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C. A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia. Heart Rhythm 17: 296-304, 2020. [PubMed: 31437535] [Full Text: https://doi.org/10.1016/j.hrthm.2019.08.018]
Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum. Molec. Genet. 21: 2759-2767, 2012. [PubMed: 22422768] [Full Text: https://doi.org/10.1093/hmg/dds104]
Shen, X., Franzini-Armstrong, C., Lopez, J. R., Jones, L. R., Kobayashi, Y. M., Wang, Y., Kerrick, W. G. L., Caswell, A. H., Potter, J. D., Miller, T., Allen, P. D., Perez, C. F. Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle. J. Biol. Chem. 282: 37864-37874, 2007. [PubMed: 17981799] [Full Text: https://doi.org/10.1074/jbc.M705702200]
Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S. Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23. Europ. J. Biochem. 233: 258-265, 1995. [PubMed: 7588753] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.258_1.x]
Thevenon, D., Smida-Rezgui, S., Chevessier, F., Groh, S., Henry-Berger, J., Romero, N. B., Villaz, M., DeWaard, M., Marty, I. Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51. Biochem. Biophys. Res. Commun. 303: 669-675, 2003. [PubMed: 12659871] [Full Text: https://doi.org/10.1016/s0006-291x(03)00406-6]
Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A. Compound heterozygous triadin mutation causing cardiac arrest in two siblings. Pacing Clin. Electrophysiol. 39: 497-501, 2016. [PubMed: 26768964] [Full Text: https://doi.org/10.1111/pace.12813]