Novel and heteroplasmic mutations in mitochondrial tRNA genes in Brugada syndrome
Abstract
Background: Brugada syndrome (BrS) is a rare cardiac arrhythmia characterized by sudden death associated with electrocardiogram patterns characterized by incomplete right bundle-branch block and ST-segment elevations in the anterior precordial leads. This syndrome predominantly is seen in younger males with structurally normal hearts. Mitochondrial variants particularly mt-tRNA mutations, are hot spots that lead to cardiological disorders. Previous studies have shown that mutations in mitochondrial tRNA genes play an important causal or modifying role in BrS. The present study aims to evaluate the involvement of mitochondrial tRNA genes in arrhythmogenic BrS.
Methods: In this study, 40 Iranian patients were investigated for the presence of the mutations in 6 mitochondrial tRNA genes (tRNA Ile, Met, Gln, Asn, Ala and Trp) by PCR-SSCP analysis.
Results: There were 4 mutations in tRNA genes, that for first time, were found in BrS patients and these mutations were not in controls. Three of them were heteroplasmic and located in tRNAGln (T4377A) and tRNAMet (G4407A and C4456T) which were assessed as pathogenic mutations. A homoplasmic variant (5580T > C) in tRNATrp gene was located within the junction region between tRNATrp and tRNAAla genes. This mutation may disturb the processing of mt-tRNATrp.
Conclusions: The results of this study suggest that mutations in mitochondrial tRNA genes might lead to deficiencies in translational process of critical proteins of the respiratory chain and potentially lead to BrS in Iranian subjects. (Cardiol J 2018; 25, 1: 113–119)
Keywords: cardiac arrhythmiaBrugada syndromemitochondrial tRNAsvariations
References
- Tokioka K, Kusano KF, Morita H, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol. 2014; 63(20): 2131–2138.
- Gourraud JB, Barc J, Thollet A, et al. The Brugada syndrome: a rare arrhythmia disorder with complex inheritance. Front Cardiovasc Med. 2016; 3: 9.
- Vohra J, Rajagopalan S. CSANZ Genetics Council Writing Group. Update on the diagnosis and management of Brugada syndrome. Heart Lung Circ. 2015; 24(12): 1141–1148.
- Sarquella-Brugada G, Campuzano O, Arbelo E, et al. Brugada syndrome: clinical and genetic findings. Genet Med. 2016; 18(1): 3–12.
- Steinfurt J, Biermann J, Bode C, et al. The Diagnosis, Risk Stratification, and Treatment of Brugada Syndrome. Dtsch Arztebl Int. 2015; 112(23): 394–401.
- Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006; 29(10): 1130–159.
- Watanabe H, Minamino T. Genetics of Brugada syndrome. J Hum Genet. 2016; 61(1): 57–60.
- Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005; 111(5): 659–670.
- Juang JMJ, Horie M. Genetics of Brugada syndrome. J Arrhythm. 2016; 32(5): 418–425.
- Nielsen MW, Holst AG, Olesen SP, et al. The genetic component of Brugada syndrome. Front Physiol. 2013; 4: 179.
- Gussak I, Antzelevitch C, Bjerregaard P, et al. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol. 1999; 33(1): 5–15.
- Remme CA. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J Physiol. 2013; 591(17): 4099–4116.
- Gustafsson AB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res. 2008; 77(2): 334–343.
- Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013; 113(6): 709–724.
- Zhu HY, Wang SW, Liu Li, et al. Genetic variants in mitochondrial tRNA genes are associated with essential hypertension in a Chinese Han population. Clin Chim Acta. 2009; 410(1-2): 64–69.
- Wilde AAM, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002; 106(19): 2514–2519.
- Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol. 2013; 61(6): 599–610.
- Ling J, Roy H, Qin D, et al. Pathogenic mechanism of a human mitochondrial tRNAPhe mutation associated with myoclonic epilepsy with ragged red fibers syndrome. Proc Natl Acad Sci U S A. 2007; 104(39): 15299–15304.
- Levinger L, Jacobs O, James M. In vitro 3'-end endonucleolytic processing defect in a human mitochondrial tRNA(Ser(UCN)) precursor with the U7445C substitution, which causes non-syndromic deafness. Nucleic Acids Res. 2001; 29(21): 4334–4340.
- Zifa E, Giannouli S, Theotokis P, et al. Mitochondrial tRNA mutations: clinical and functional perturbations. RNA Biol. 2007; 4(1): 38–66.
- Khatami F. Mehdi Heidari M, Houshmand M. The mitochondrial DNA mutations associated with cardiac arrhythmia investigated in an LQTS family. Iran J Basic Med Sci. 2014; 17(9): 656–661.
- Khatami M, Houshmand M, Sadeghizadeh M, et al. Accumulation of mitochondrial genome variations in Persian LQTS patients: a possible risk factor? Cardiovasc Pathol. 2010; 19(2): e21–e27.
- Stocchi L, Polidori E, Potenza L, et al. Mutational analysis of mitochondrial DNA in Brugada syndrome. Cardiovasc Pathol. 2016; 25(1): 47–54.
- Helm M, Brulé H, Friede D, et al. Search for characteristic structural features of mammalian mitochondrial tRNAs. RNA. 2000; 6(10): 1356–1379.
- Jones CN, Jones CI, Graham WD, et al. A disease-causing point mutation in human mitochondrial tRNAMet rsults in tRNA misfolding leading to defects in translational initiation and elongation. J Biol Chem. 2008; 283(49): 34445–34456.
- Holzmann J, Frank P, Löffler E, et al. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell. 2008; 135(3): 462–474.
- Levinger L, Mörl M, Florentz C. Mitochondrial tRNA 3' end metabolism and human disease. Nucleic Acids Res. 2004; 32(18): 5430–5441.
