Variants in the 3′ untranslated region of the KCNQ1-encoded K v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner

Ahmad S. Amin, John R. Giudicessi, Anke J. Tijsen, Anne M. Spanjaart, Yolan J. Reckman, Christine A. Klemens, Michael W. Tanck, Jamie D. Kapplinger, Nynke Hofman, Moritz F. Sinner, Martina Mller, Wino J. Wijnen, Hanno L. Tan, Connie R. Bezzina, Esther E. Creemers, Arthur A M Wilde, Michael John Ackerman, Yigal M. Pinto

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1s 3′ untranslated region (3′UTR).Methods and resultsThis study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1s 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1s 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants. Conclusion Our data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.

Original languageEnglish (US)
Pages (from-to)714-723
Number of pages10
JournalEuropean Heart Journal
Volume33
Issue number6
DOIs
StatePublished - Mar 2012

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Romano-Ward Syndrome
Potassium Channels
3' Untranslated Regions
Single Nucleotide Polymorphism
Alleles
Mutation
Penetrance
Luciferases
Cardiac Arrhythmias

Keywords

  • 3′ untranslated region
  • KCNQ1
  • Long QT syndrome
  • QTc
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Variants in the 3′ untranslated region of the KCNQ1-encoded K v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. / Amin, Ahmad S.; Giudicessi, John R.; Tijsen, Anke J.; Spanjaart, Anne M.; Reckman, Yolan J.; Klemens, Christine A.; Tanck, Michael W.; Kapplinger, Jamie D.; Hofman, Nynke; Sinner, Moritz F.; Mller, Martina; Wijnen, Wino J.; Tan, Hanno L.; Bezzina, Connie R.; Creemers, Esther E.; Wilde, Arthur A M; Ackerman, Michael John; Pinto, Yigal M.

In: European Heart Journal, Vol. 33, No. 6, 03.2012, p. 714-723.

Research output: Contribution to journalArticle

Amin, AS, Giudicessi, JR, Tijsen, AJ, Spanjaart, AM, Reckman, YJ, Klemens, CA, Tanck, MW, Kapplinger, JD, Hofman, N, Sinner, MF, Mller, M, Wijnen, WJ, Tan, HL, Bezzina, CR, Creemers, EE, Wilde, AAM, Ackerman, MJ & Pinto, YM 2012, 'Variants in the 3′ untranslated region of the KCNQ1-encoded K v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner', European Heart Journal, vol. 33, no. 6, pp. 714-723. https://doi.org/10.1093/eurheartj/ehr473
Amin, Ahmad S. ; Giudicessi, John R. ; Tijsen, Anke J. ; Spanjaart, Anne M. ; Reckman, Yolan J. ; Klemens, Christine A. ; Tanck, Michael W. ; Kapplinger, Jamie D. ; Hofman, Nynke ; Sinner, Moritz F. ; Mller, Martina ; Wijnen, Wino J. ; Tan, Hanno L. ; Bezzina, Connie R. ; Creemers, Esther E. ; Wilde, Arthur A M ; Ackerman, Michael John ; Pinto, Yigal M. / Variants in the 3′ untranslated region of the KCNQ1-encoded K v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. In: European Heart Journal. 2012 ; Vol. 33, No. 6. pp. 714-723.
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abstract = "Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1s 3′ untranslated region (3′UTR).Methods and resultsThis study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1s 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1s 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants. Conclusion Our data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.",
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T1 - Variants in the 3′ untranslated region of the KCNQ1-encoded K v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner

AU - Amin, Ahmad S.

AU - Giudicessi, John R.

AU - Tijsen, Anke J.

AU - Spanjaart, Anne M.

AU - Reckman, Yolan J.

AU - Klemens, Christine A.

AU - Tanck, Michael W.

AU - Kapplinger, Jamie D.

AU - Hofman, Nynke

AU - Sinner, Moritz F.

AU - Mller, Martina

AU - Wijnen, Wino J.

AU - Tan, Hanno L.

AU - Bezzina, Connie R.

AU - Creemers, Esther E.

AU - Wilde, Arthur A M

AU - Ackerman, Michael John

AU - Pinto, Yigal M.

PY - 2012/3

Y1 - 2012/3

N2 - Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1s 3′ untranslated region (3′UTR).Methods and resultsThis study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1s 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1s 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants. Conclusion Our data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.

AB - Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1s 3′ untranslated region (3′UTR).Methods and resultsThis study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1s 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1s 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants. Conclusion Our data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.

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KW - KCNQ1

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KW - QTc

KW - Single nucleotide polymorphism

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