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The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death.

Shi R, Zhang Y, Yang C, Huang C, Zhou X, Qiang H, Grace AA, Huang CL, Ma A - Europace (2008)

Bottom Line: Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function.Two additional subjects died suddenly at 13 and 33 years.This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Paediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China.

ABSTRACT

Aim: We report diverse phenotypic consequences of the delQKP-1507-1509 cardiac sodium channel mutation in three generations of a Chinese family.

Methods and results: Clinical and electrocardiographic (ECG), echocardiographic examination was followed by direct sequencing of SCN5A, KCNQ1, HERG, and LAMIN A/C to screen genomic DNA from blood samples. Of two mutation carriers, the proband was born with conduction disorders including second-degree atrioventricular (AV) block with prolonged QTc interval, additionally showing left anterior fascicular block (LAFB), incomplete right bundle-branch block (IRBBB), and intermittent third-degree AV block at 2 years, and clinical presentations of multiple syncope despite normal electroencephalograms at 8 years. Continuous ECG monitoring following presentation at 13 years revealed prolonged QTc and biphasic T-waves, multiple episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function. Another mutation carrier showed features of long QT syndrome type 3 (LQT3), LAFB, and dilated cardiomyopathy (DCM). Two additional subjects died suddenly at 13 and 33 years.

Conclusion: This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

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Related in: MedlinePlus

delQKP1507–1509 mutation of SCN5A sodium channel. (A) A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A resulting in the deletion of three amino acids QKP Gln1507–Lys1508–Pro1509 compared with the corresponding control segments (B) of exon 26 of SCN5A. (C) SSCP confirmed two mutation carriers (proband and subject I-2). No labelled bands are control samples. (D) Position of the delQKP1507–1509 mutation on Nav1.5 channel.
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EUN202F3: delQKP1507–1509 mutation of SCN5A sodium channel. (A) A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A resulting in the deletion of three amino acids QKP Gln1507–Lys1508–Pro1509 compared with the corresponding control segments (B) of exon 26 of SCN5A. (C) SSCP confirmed two mutation carriers (proband and subject I-2). No labelled bands are control samples. (D) Position of the delQKP1507–1509 mutation on Nav1.5 channel.

Mentions: A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A (Figure 3A), corresponding to the three amino acid residues Gln1507–Lys1508–Pro1509 (QKP) was found (Figure 3B) in the proband (subject III-2) and his grandmother (subject I-2) and excluded in the remaining living subjects in this family. This mutation was confirmed using SSCP (Figure 3C). The inframe-deletion disrupts the coding sequence of QKP at the terminal part of exon 26 and is localized in the linker region between DIII and DIV of the Nav1.5 sodium channel (Figure 3D). Similar analysis excluded possible mutations that would lead to amino acid changes in KCNQ1, HERG, and LAMIN A/C commonly associated with LQT1, LQT2, and DCM with conduction disorders on earlier occasions:11–13 we did not find new mutations that would lead to amino acid changes. Three base substitutions were observed in HERG: 1480C→T, 1552C→T, and 1705A→G, but these would not have altered the encoded amino acid.


The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death.

Shi R, Zhang Y, Yang C, Huang C, Zhou X, Qiang H, Grace AA, Huang CL, Ma A - Europace (2008)

delQKP1507–1509 mutation of SCN5A sodium channel. (A) A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A resulting in the deletion of three amino acids QKP Gln1507–Lys1508–Pro1509 compared with the corresponding control segments (B) of exon 26 of SCN5A. (C) SSCP confirmed two mutation carriers (proband and subject I-2). No labelled bands are control samples. (D) Position of the delQKP1507–1509 mutation on Nav1.5 channel.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2573028&req=5

EUN202F3: delQKP1507–1509 mutation of SCN5A sodium channel. (A) A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A resulting in the deletion of three amino acids QKP Gln1507–Lys1508–Pro1509 compared with the corresponding control segments (B) of exon 26 of SCN5A. (C) SSCP confirmed two mutation carriers (proband and subject I-2). No labelled bands are control samples. (D) Position of the delQKP1507–1509 mutation on Nav1.5 channel.
Mentions: A heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26 of SCN5A (Figure 3A), corresponding to the three amino acid residues Gln1507–Lys1508–Pro1509 (QKP) was found (Figure 3B) in the proband (subject III-2) and his grandmother (subject I-2) and excluded in the remaining living subjects in this family. This mutation was confirmed using SSCP (Figure 3C). The inframe-deletion disrupts the coding sequence of QKP at the terminal part of exon 26 and is localized in the linker region between DIII and DIV of the Nav1.5 sodium channel (Figure 3D). Similar analysis excluded possible mutations that would lead to amino acid changes in KCNQ1, HERG, and LAMIN A/C commonly associated with LQT1, LQT2, and DCM with conduction disorders on earlier occasions:11–13 we did not find new mutations that would lead to amino acid changes. Three base substitutions were observed in HERG: 1480C→T, 1552C→T, and 1705A→G, but these would not have altered the encoded amino acid.

Bottom Line: Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function.Two additional subjects died suddenly at 13 and 33 years.This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Paediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China.

ABSTRACT

Aim: We report diverse phenotypic consequences of the delQKP-1507-1509 cardiac sodium channel mutation in three generations of a Chinese family.

Methods and results: Clinical and electrocardiographic (ECG), echocardiographic examination was followed by direct sequencing of SCN5A, KCNQ1, HERG, and LAMIN A/C to screen genomic DNA from blood samples. Of two mutation carriers, the proband was born with conduction disorders including second-degree atrioventricular (AV) block with prolonged QTc interval, additionally showing left anterior fascicular block (LAFB), incomplete right bundle-branch block (IRBBB), and intermittent third-degree AV block at 2 years, and clinical presentations of multiple syncope despite normal electroencephalograms at 8 years. Continuous ECG monitoring following presentation at 13 years revealed prolonged QTc and biphasic T-waves, multiple episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function. Another mutation carrier showed features of long QT syndrome type 3 (LQT3), LAFB, and dilated cardiomyopathy (DCM). Two additional subjects died suddenly at 13 and 33 years.

Conclusion: This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

Show MeSH
Related in: MedlinePlus