- Email: [email protected]
A novel mutation (Arg169Gln) of the cardiac ryanodine receptor gene causing exercise-induced bidirectional ventricular tachycardia
International Journal of Cardiology 108 (2006) 276 – 278 www.elsevier.com/locate/ijcard
Letter to the Editor
A novel mutation (Arg169Gln) of the cardiac ryanodine receptor gene causing exercise-induced bidirectional ventricular tachycardia Chia-Hsiang Hsueha, Yi-Chun Wenga, Chao-Yu Chena, Tin-Kwang Linb, Yen-Hung Linc, Ling-Ping Laia, Jiunn-Lee Linc,* a Institute of Pharmacology, School of Medicine, National Taiwan University, Taipei, Taiwan Cardiovascular Division, Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Dalin, Taiwan c Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan S Rd., Taipei, Taiwan b
Received 14 February 2005; received in revised form 19 February 2005 Available online 27 April 2005
Abstract An 18-year-old woman presented with exercise induced sudden collapse. Series of cardiac work up revealed no structural cardiac abnormalities. Bidirectional ventricular tachycardia occurred during a treadmill exercise test. Under the impression of catecholaminergic polymorphic ventricular tachycardia, we screened the cardiac ryanodine receptor gene for mutation. We identified a novel heterozygous mutation at the 169th amino acid (Arg169Gln). This amino acid is highly conserved among many species and this mutation was not present in 50 normal control subjects. This patient was treated with a h-block with good response. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac ryanodine receptor; Catecholaminergic polymorphic ventricular tachycardia; Sudden cardiac death
An 18-year-old woman presented with sudden collapse during an outdoor physical training course. She was resuscitated on the spot with an automated external defibrillator and had a full recovery. She underwent series of cardiac work up and there was no any structural abnormalities found. The resting ECG was normal and revealed no evidence of long QT syndrome or Brugada syndrome. A treadmill exercise test was performed to exclude the possibility of catecholaminergic polymorphic ventricular tachycardia [1]. After 1 min of exercise, bidirectional ventricular tachycardia occurred (Fig. 1). Mutation screening of the cardiac ryanodine receptor was performed. Polymerase chain reactions were performed to amplify exons 8, 14, 15, 44, 47, 49, 90, 93, 95, 102 because these exons are mutation hot regions. We found a heterozygous base substitution in exon 8 at the 506th nucleotide. This substitution resulted in an amino acid change from T Corresponding author. Tel.: +886 2 23123456x5001; fax: +886 2 23951841. E-mail address: [email protected] (J.-L. Lin). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.02.051
arginin to glutamin at the 169th position (Fig. 2). The arginin at the 169th position is highly conserved among many species and it locates within the mutation hot regions of the cardiac ryanodine receptor gene. Further polymerase chain reaction and restriction fragment analysis revealed that this mutation was absent in 50 control subjects (100 alleles), who had no clinical arrhythmias. Therefore, this point mutation was not likely a single nucleotide polymorphism. The final diagnosis for the patient was catecholaminergic polymorphic ventricular tachycardia due to cardiac ryanodine receptor mutation. Implantation of an implantable cardioverter defibrillator was advised but the patient refused. She was placed on long-term h-blocker therapy and was free of symptoms at follow-up. Ryanodine receptors are intracellular calcium channels that regulate the release of calcium from the endoplasmic or sarcoplasmic reticulum of many cell types [2]. There are three isoforms of ryanodine receptor in human: the skeletal muscle ryanodine receptor (type 1), cardiac ryanodine receptor (type 2) and brain ryanodine receptor (type 3). In cardiac muscle, the type 2 ryanodine receptors (RYR2) are
C.-H. Hsueh et al. / International Journal of Cardiology 108 (2006) 276 – 278
277
Fig. 1. Bidirectional ventricular tachycardia in an 18-year-old woman without structural heart disease. This patient had normal ECG at rest and developed bidirectional ventricular tachycardia during a treadmill exercise test. This is compatible with the diagnosis of catecholaminergic polymorphic ventricular tachycardia.
Fig. 2. DNA and amino acid sequence of cardiac ryanodine receptor exon 8 in an 18-year-old woman with catecholaminergic polymorphic ventricular tachycardia. A heterozygous mis-sense mutation was identified causing an amino acid change from arginin to glutamine.
responsible for calcium-induced calcium release from the sarcoplasmic reticulum. They therefore play important roles in the excitation – contraction coupling process of the myocardium. The RYR2 gene is one of the largest genes in human genome. It contains 105 exons and encodes an mRNA of greater than 15,000 bases [3]. RYR2 mutations with altered calcium release properties have been identified in patients with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia [4– 6]. Both diseases result in a high risk of sudden cardiac death in affected individuals. The identification of the mutations in RYR2 gene is therefore important for the diagnosis and screening of such diseases. In the present study, we screened the mutation in the RYR2 gene in a patient with catecholaminergic polymorphic ventricular tachycardia.
We found a heterozygous mutation in exon 8 (Arg169Gln). This mutation has never been reported before and can be added to the compendium of mutations responsible for sudden cardiac death.
References [1] Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512 – 9. [2] Ogawa Y, Kurebayashi N, Murayama T. Ryanodine receptor isoforms in excitation – contraction coupling. Adv Biophys 1999;36:27 – 64. [3] Tunwell RE, Wickenden C, Bertrand BM, et al. The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis. Biochem J 1996; 318:477 – 787.
278
C.-H. Hsueh et al. / International Journal of Cardiology 108 (2006) 276 – 278
[4] Marks AR, Priori S, Memmi M, et al. Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. J Cell Physiol 2001;190:1 – 6. [5] Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmo-
genic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10:189 – 94. [6] Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196 – 200.
Letter to the Editor
A novel mutation (Arg169Gln) of the cardiac ryanodine receptor gene causing exercise-induced bidirectional ventricular tachycardia Chia-Hsiang Hsueha, Yi-Chun Wenga, Chao-Yu Chena, Tin-Kwang Linb, Yen-Hung Linc, Ling-Ping Laia, Jiunn-Lee Linc,* a Institute of Pharmacology, School of Medicine, National Taiwan University, Taipei, Taiwan Cardiovascular Division, Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Dalin, Taiwan c Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan S Rd., Taipei, Taiwan b
Received 14 February 2005; received in revised form 19 February 2005 Available online 27 April 2005
Abstract An 18-year-old woman presented with exercise induced sudden collapse. Series of cardiac work up revealed no structural cardiac abnormalities. Bidirectional ventricular tachycardia occurred during a treadmill exercise test. Under the impression of catecholaminergic polymorphic ventricular tachycardia, we screened the cardiac ryanodine receptor gene for mutation. We identified a novel heterozygous mutation at the 169th amino acid (Arg169Gln). This amino acid is highly conserved among many species and this mutation was not present in 50 normal control subjects. This patient was treated with a h-block with good response. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac ryanodine receptor; Catecholaminergic polymorphic ventricular tachycardia; Sudden cardiac death
An 18-year-old woman presented with sudden collapse during an outdoor physical training course. She was resuscitated on the spot with an automated external defibrillator and had a full recovery. She underwent series of cardiac work up and there was no any structural abnormalities found. The resting ECG was normal and revealed no evidence of long QT syndrome or Brugada syndrome. A treadmill exercise test was performed to exclude the possibility of catecholaminergic polymorphic ventricular tachycardia [1]. After 1 min of exercise, bidirectional ventricular tachycardia occurred (Fig. 1). Mutation screening of the cardiac ryanodine receptor was performed. Polymerase chain reactions were performed to amplify exons 8, 14, 15, 44, 47, 49, 90, 93, 95, 102 because these exons are mutation hot regions. We found a heterozygous base substitution in exon 8 at the 506th nucleotide. This substitution resulted in an amino acid change from T Corresponding author. Tel.: +886 2 23123456x5001; fax: +886 2 23951841. E-mail address: [email protected] (J.-L. Lin). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.02.051
arginin to glutamin at the 169th position (Fig. 2). The arginin at the 169th position is highly conserved among many species and it locates within the mutation hot regions of the cardiac ryanodine receptor gene. Further polymerase chain reaction and restriction fragment analysis revealed that this mutation was absent in 50 control subjects (100 alleles), who had no clinical arrhythmias. Therefore, this point mutation was not likely a single nucleotide polymorphism. The final diagnosis for the patient was catecholaminergic polymorphic ventricular tachycardia due to cardiac ryanodine receptor mutation. Implantation of an implantable cardioverter defibrillator was advised but the patient refused. She was placed on long-term h-blocker therapy and was free of symptoms at follow-up. Ryanodine receptors are intracellular calcium channels that regulate the release of calcium from the endoplasmic or sarcoplasmic reticulum of many cell types [2]. There are three isoforms of ryanodine receptor in human: the skeletal muscle ryanodine receptor (type 1), cardiac ryanodine receptor (type 2) and brain ryanodine receptor (type 3). In cardiac muscle, the type 2 ryanodine receptors (RYR2) are
C.-H. Hsueh et al. / International Journal of Cardiology 108 (2006) 276 – 278
277
Fig. 1. Bidirectional ventricular tachycardia in an 18-year-old woman without structural heart disease. This patient had normal ECG at rest and developed bidirectional ventricular tachycardia during a treadmill exercise test. This is compatible with the diagnosis of catecholaminergic polymorphic ventricular tachycardia.
Fig. 2. DNA and amino acid sequence of cardiac ryanodine receptor exon 8 in an 18-year-old woman with catecholaminergic polymorphic ventricular tachycardia. A heterozygous mis-sense mutation was identified causing an amino acid change from arginin to glutamine.
responsible for calcium-induced calcium release from the sarcoplasmic reticulum. They therefore play important roles in the excitation – contraction coupling process of the myocardium. The RYR2 gene is one of the largest genes in human genome. It contains 105 exons and encodes an mRNA of greater than 15,000 bases [3]. RYR2 mutations with altered calcium release properties have been identified in patients with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia [4– 6]. Both diseases result in a high risk of sudden cardiac death in affected individuals. The identification of the mutations in RYR2 gene is therefore important for the diagnosis and screening of such diseases. In the present study, we screened the mutation in the RYR2 gene in a patient with catecholaminergic polymorphic ventricular tachycardia.
We found a heterozygous mutation in exon 8 (Arg169Gln). This mutation has never been reported before and can be added to the compendium of mutations responsible for sudden cardiac death.
References [1] Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512 – 9. [2] Ogawa Y, Kurebayashi N, Murayama T. Ryanodine receptor isoforms in excitation – contraction coupling. Adv Biophys 1999;36:27 – 64. [3] Tunwell RE, Wickenden C, Bertrand BM, et al. The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis. Biochem J 1996; 318:477 – 787.
278
C.-H. Hsueh et al. / International Journal of Cardiology 108 (2006) 276 – 278
[4] Marks AR, Priori S, Memmi M, et al. Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. J Cell Physiol 2001;190:1 – 6. [5] Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmo-
genic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10:189 – 94. [6] Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196 – 200.