The TECRL gene encodes an integral membrane protein with oxidoreductase activity. The protein consists of a ubiquitin-like domain at the N-terminal, a 3-oxo-5-alpha steroid 4-dehydrogenase domain at the C-terminal and 3 transmembrane regions. While the specific function of TECRL is yet to be elucidated, it is believed to play a role in the biosynthesis of very long chain fatty acids.
Recent knockdown studies using sh-RNA have further illuminated the physiological role of TECRL. It was found that knockdown of TECRL in human embryonic stem cell-derived cardiomyocytes resulted in significantly prolonged action potentials. It also reduced cell content of the canonical calcium-handling proteins RYR2 and CASQ2. The gene has been implicated in Ventricular Tachycardia, Catecholaminergic Polymorphic, 3 (CPVT3), an arrhythmia characterized by the overlapping features of CPVT and Long QT Syndrome.
The TECRL gene is located on the long arm of chromosome 4. It spans a length of 134 kb of DNA and its coding sequence is spread across 15 exons. The gene encodes a 42 kDa protein product consisting of 363 amino acids. TECRL is found to be expressed in the heart and skeletal muscle alone. Variants in TECRL associated with CPVT3 include a missense mutation (R196Q) and a splice-site mutation (c.331+1G-A). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the splice-site mutation have been found to exhibit electrophysiological and calcium-handling abnormalities as well as an increased susceptibility to triggered electrical activity upon catecholaminergic stimulation by noradrenaline.
Devalla et al. (2016) analyzed a multiplex consanguineous Sudanese family in which seven children suffered exertion-induced arrhythmias and/or sudden cardiac death (SCD) during early childhood. The patients were found to have CPVT with prolongation of the QT interval. The authors identified a homozygous splice site mutation (c.331+1G>A) in the TECRL gene of affected members. The variant was located in the splice donor site of intron 3 resulting in an internal deletion in the putative ubiquitin-like domain. The parents of the proband were heterozygous for the variant. It was not seen in dbSNP, 1000 Genomes, 6500 NHLBI, ExAC, in-house databases or in 72 Saudi Arab controls. Using patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), it was seen that the variant resulted in complete skipping of exon 3. Further, compared to controls, the mutant cardiomyocytes exhibited electrophysiological and calcium-handling abnormalities. They were also prone to an increase in triggered electrical activity upon noradrenaline stimulation which could be significantly reduced by treatment with flecainide, a class Ic antiarrhythmic drug.
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to email@example.com.