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.
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