Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy.

Junbo Ge, Aijun Sun, Vesa Paajanen, Shijun Wang, Chunxi Su, Zhiyin Yang, Ying Li, Shaochun Wang, Jianguo Jia, Keqiang Wang, Yunzeng Zou, Lizhi Gao, Kun Wang, Zheng Fan

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.

Original languageEnglish (US)
Pages (from-to)83-92
Number of pages10
JournalCirculation. Arrhythmia and electrophysiology
Volume1
Issue number2
DOIs
StatePublished - Jan 1 2008

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Atrioventricular Block
Dilated Cardiomyopathy
Mutation
Phenotype
Penetrance
Amino Acid Substitution
Heart Diseases
Electrocardiography
Reference Values
Homeostasis
Nucleotides
Chromosomes
Heart Rate
Genes
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy. / Ge, Junbo; Sun, Aijun; Paajanen, Vesa; Wang, Shijun; Su, Chunxi; Yang, Zhiyin; Li, Ying; Wang, Shaochun; Jia, Jianguo; Wang, Keqiang; Zou, Yunzeng; Gao, Lizhi; Wang, Kun; Fan, Zheng.

In: Circulation. Arrhythmia and electrophysiology, Vol. 1, No. 2, 01.01.2008, p. 83-92.

Research output: Contribution to journalArticle

Ge, Junbo ; Sun, Aijun ; Paajanen, Vesa ; Wang, Shijun ; Su, Chunxi ; Yang, Zhiyin ; Li, Ying ; Wang, Shaochun ; Jia, Jianguo ; Wang, Keqiang ; Zou, Yunzeng ; Gao, Lizhi ; Wang, Kun ; Fan, Zheng. / Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy. In: Circulation. Arrhythmia and electrophysiology. 2008 ; Vol. 1, No. 2. pp. 83-92.
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T1 - Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy.

AU - Ge, Junbo

AU - Sun, Aijun

AU - Paajanen, Vesa

AU - Wang, Shijun

AU - Su, Chunxi

AU - Yang, Zhiyin

AU - Li, Ying

AU - Wang, Shaochun

AU - Jia, Jianguo

AU - Wang, Keqiang

AU - Zou, Yunzeng

AU - Gao, Lizhi

AU - Wang, Kun

AU - Fan, Zheng

PY - 2008/1/1

Y1 - 2008/1/1

N2 - BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.

AB - BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.

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JO - Circulation: Arrhythmia and Electrophysiology

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SN - 1941-3149

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