Alternative titles; symbols
HGNC Approved Gene Symbol: TECRL
Cytogenetic location: 4q13.1 Genomic coordinates (GRCh38) : 4:64,276,298-64,409,460 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q13.1 | Ventricular tachycardia, catecholaminergic polymorphic, 3 | 614021 | Autosomal recessive | 3 |
TECRL is an endoplasmic reticulum (ER) protein expressed preferentially in the heart (summary by Xie et al., 2019)..
Devalla et al. (2016) stated that TECRL encodes a deduced 363-amino acid protein with an N-terminal ubiquitin-like domain, 3 transmembrane regions, and a C-terminal 3-oxo-5-alpha steroid 4-dehydrogenase domain. The last 2 transmembrane regions overlap with the 3-oxo-5-alpha steroid 4-dehydrogenase domain. Quantitative RT-PCR detected highest TECRL expression in heart and skeletal muscle, with little to no expression in other human tissues examined. In adult mouse tissues, Tecrl was detected in heart, but not in other tissues examined, including skeletal muscle. In situ hybridization of developing mouse detected Tecrl expression beginning at embryonic day 8.5 in heart, with strongest expression in the left horn of the developing inflow tract. At embryonic day 10 onward, low Tecrl expression was also detected in somites. Epitope-tagged mouse Tecrl was expressed in endoplasmic reticulum of transfected COS-1 and H10 cells.
Devalla et al. (2016) reported that the TECRL gene has 12 exons and spans 134 kb.
Devalla et al. (2016) stated that the TECRL gene maps to chromosome 4q13.1.
Using human embryonic stem cell-derived cardiomyocytes, Devalla et al. (2016) found that knockdown of TECRL via short hairpin RNA had no effect on the cardiac phenotype of the cells, but it prolonged an induced action potential. Western blot analysis showed that knockdown of TECRL reduced cell content of the canonical calcium-handling proteins RYR2 (180902) and CASQ2 (114251).
In a Sudanese kindred with catecholaminergic polymorphic ventricular tachycardia and prolongation of the QT interval (CPVT3; 614021), Devalla et al. (2016) identified homozygosity for a splice site mutation in the TECRL gene (617242.0001) that segregated fully with disease. In 2 unrelated French Canadian women with CPVT3, the authors identified homozygosity for a missense mutation in TECRL (R196Q; 617242.0002). Analysis of intracellular calcium dynamics in patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed prolongation of the action potential, alterations in calcium handling, and increased propensity for delayed after-depolarizations during catecholaminergic stimulation, compared to control iPSC-CMs.
In a 13-year-old boy with CPVT3, Xie et al. (2019) identified compound heterozygosity in the TECRL gene: the previously reported R196Q mutation inherited from his unaffected mother and a novel splice site mutation (617242.0003) inherited from his unaffected father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The proband's older brother had experienced sudden death at 12 years of age but his DNA was not available for testing.
In 6 affected children with catecholaminergic polymorphic ventricular tachycardia and prolongation of the QT interval (CPVT3; 614021) from a Sudanese kindred originally reported by Bhuiyan et al. (2007), Devalla et al. (2016) identified homozygosity for a c.331+1G-A transition (c.331+1G-A, NM_001010874.4) at the splice donor site of intron 3 of the TECRL gene. The mutation was present in heterozygosity in the parents and in 2 unaffected sibs; it was not found in 72 Saudi Arabian controls, in-house databases, or in the dbSNP, 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. PCR analysis of cDNA from patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) indicated that the mutation causes complete skipping of exon 3. Analysis of intracellular calcium dynamics in iPSC-CMs revealed smaller transient amplitudes as well as elevated diastolic levels of intracellular Ca(2+) in patient-derived cardiomyocytes compared to controls; the intracellular Ca(2+) transient also rose markedly slower and there were lower sarcoplasmic reticulum calcium stores in patient iPSC-CMs compared to controls. In addition, the decay phase of the Ca(2+) transient was slower in patient iPSC-CMs due to decreased SERCA (see 108730) and NCX (604240) activity, and patient-derived cardiomyocytes also showed prolonged action potentials compared to controls. Stimulation by noradrenaline significantly increased the propensity for triggered activity based on delayed after-depolarizations in patient iPSC-CMs.
In 2 unrelated French Canadian women with catecholaminergic polymorphic ventricular tachycardia and prolongation of the QT interval (CPVT3; 614021), Devalla et al. (2016) identified homozygosity for a G-A transition (NM_001010874.4) in exon 6 of the TECRL gene, resulting in an arg196-to-gln (R196Q) substitution. The mutation was not found in 540 European-derived chromosomes; DNA was unavailable from family members.
In a 13-year-old boy with CPVT3, Xie et al. (2019) identified compound heterozygosity for mutations in the TECRL gene: the R196Q mutation and a splice site mutation (c.918+3G-T; 617242.0003) between the 9th and 10th exons. The unaffected parents were each heterozygous for one of the mutations. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The proband's older brother had experienced sudden death at 12 years of age but his DNA was not available for testing.
For discussion of the splice site mutation (c.918+3T-G, NM_001010874.4) in intron 9 of the TECRL gene that was identified in compound heterozygous state in a boy with catecholaminergic polymorphic ventricular tachycardia-3 (CPVT3; 614021) by Xie et al. (2019), see 617242.0002.
Bhuiyan, Z. A., Hamdan, M. A., Shamsi, E. T. A., Postma, A. V., Mannens, M. M. A. M., Wilde, A. A. M., Al-Gazali, L. A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. J. Cardiovasc. Electrophysiol. 18: 1060-1066, 2007. [PubMed: 17666061] [Full Text: https://doi.org/10.1111/j.1540-8167.2007.00913.x]
Devalla, H. D., Gelinas, R., Aburawi, E. H., Beqqali, A., Goyette, P., Freund, C., Chaix, M.-A., Tadros, R., Jiang, H., Le Bechec, A., Monshouwer-Kloots, J. J., Zwetsloot, T., and 17 others. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Molec. Med. 8: 1390-1408, 2016. [PubMed: 27861123] [Full Text: https://doi.org/10.15252/emmm.201505719]
Xie, L., Hou, C., Jiang, X., Zhao, J., Li, Y., Xiao, T. A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family. Europ. J. Med. Genet. 62: 103631, 2019. Note: Electronic Article. [PubMed: 30790670] [Full Text: https://doi.org/10.1016/j.ejmg.2019.01.018]