Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome

C. W. Lu, J. H. Lin, Y. S. Rajawat, H. Jerng, T. G. Rami, X. Sanchez, G. DeFreitas, B. Carabello, F. DeMayo, D. L. Kearney, G. Miller, H. Li, P. J. Pfaffinger, N. E. Bowles, D. S. Khoury, Jeffrey Towbin

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Abstract

Background: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. Methods and results: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. Conclusions: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

Original languageEnglish (US)
Pages (from-to)653-659
Number of pages7
JournalJournal of medical genetics
Volume43
Issue number8
DOIs
StatePublished - Aug 1 2006

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Andersen Syndrome
Transgenic Mice
Mutation
Xenopus
Oocytes
Inwardly Rectifying Potassium Channel
Aptitude
Missense Mutation
Ventricular Tachycardia
DNA Sequence Analysis
Tachycardia
Paralysis
Genes
Electrocardiography
Cell Membrane
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome. / Lu, C. W.; Lin, J. H.; Rajawat, Y. S.; Jerng, H.; Rami, T. G.; Sanchez, X.; DeFreitas, G.; Carabello, B.; DeMayo, F.; Kearney, D. L.; Miller, G.; Li, H.; Pfaffinger, P. J.; Bowles, N. E.; Khoury, D. S.; Towbin, Jeffrey.

In: Journal of medical genetics, Vol. 43, No. 8, 01.08.2006, p. 653-659.

Research output: Contribution to journalArticle

Lu, CW, Lin, JH, Rajawat, YS, Jerng, H, Rami, TG, Sanchez, X, DeFreitas, G, Carabello, B, DeMayo, F, Kearney, DL, Miller, G, Li, H, Pfaffinger, PJ, Bowles, NE, Khoury, DS & Towbin, J 2006, 'Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome', Journal of medical genetics, vol. 43, no. 8, pp. 653-659. https://doi.org/10.1136/jmg.2006.040816
Lu, C. W. ; Lin, J. H. ; Rajawat, Y. S. ; Jerng, H. ; Rami, T. G. ; Sanchez, X. ; DeFreitas, G. ; Carabello, B. ; DeMayo, F. ; Kearney, D. L. ; Miller, G. ; Li, H. ; Pfaffinger, P. J. ; Bowles, N. E. ; Khoury, D. S. ; Towbin, Jeffrey. / Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome. In: Journal of medical genetics. 2006 ; Vol. 43, No. 8. pp. 653-659.
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abstract = "Background: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. Methods and results: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. Conclusions: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.",
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T1 - Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome

AU - Lu, C. W.

AU - Lin, J. H.

AU - Rajawat, Y. S.

AU - Jerng, H.

AU - Rami, T. G.

AU - Sanchez, X.

AU - DeFreitas, G.

AU - Carabello, B.

AU - DeMayo, F.

AU - Kearney, D. L.

AU - Miller, G.

AU - Li, H.

AU - Pfaffinger, P. J.

AU - Bowles, N. E.

AU - Khoury, D. S.

AU - Towbin, Jeffrey

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Background: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. Methods and results: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. Conclusions: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

AB - Background: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. Methods and results: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. Conclusions: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

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