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  ANK2 functionally interacts with KCNH2 aggravating long QT syndrome in a double mutation carrier

Gessnera, G., Runge, S., Koenen, M., Heinemann, S. H., Koenen, M., Haas, J., et al. (2019). ANK2 functionally interacts with KCNH2 aggravating long QT syndrome in a double mutation carrier. Biochemical and Biophysical Research Communications, 512(4), 845-851. doi:10.1016/j.bbrc.2019.03.162.

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 Creators:
Gessnera, Guido, Author
Runge, Sarah, Author
Koenen, Michael, Author
Heinemann, Stefan H., Author
Koenen, Michael1, 2, 3, Author           
Haas, Jan, Author
Meder, Benjamin, Author
Thomas, Dierk, Author
Katus, Hugo A., Author
Schweizer, Patrick A., Author
Affiliations:
1Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              
2Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
3Abteilung Zellphysiologie, MPI for biophysical chemistry, Max Planck Society, ou_578558              

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Free keywords: ANK2; KCNH2; Long QT syndrome; Arrhythmia; Conduction disease
 Abstract: Pathogenic long QT mutations often comprise high phenotypic variability and particularly variants in ANK2 (long QT syndrome 4) frequently lack QT prolongation. We sought to elucidate the genetic and functional background underlying the clinical diversity in a 3-generation family with different cardiac arrhythmias. Next-generation sequencing-based screening of patients with QT prolongation identified the index patient of the family carrying an ANK2-E1813K variant and a previously uncharacterized KCNH2-H562R mutation in a double heterozygous conformation. The patient presented with a severe clinical phenotype including a markedly prolonged QTc interval (544 ms), recurrent syncope due to Torsade de Pointes tachycardias, survived cardiopulmonary resuscitation, progressive cardiac conduction defect, and atrial fibrillation. Evaluation of other family members identified a sister and a niece solely carrying the ANK2-E1813K variant, who showed age-related conduction disease. An asymptomatic second sister solely carried the KCNH2-H562R mutation. Voltage-clamp recordings in Xenopus oocytes revealed that KCNH2-H562R subunits were non-functional but did not exert dominant-negative effects on wild-type subunits. Expression of KCNH2-H562R in HEK293 cells showed a trafficking deficiency. Co-expression of the C-terminal regulatory domain of ANK2 in Xenopus oocytes revealed that ANK2-E1813K diminished currents mediated by the combination of wild-type and H562R KCNH2 subunits. Our data suggest that ANK2 functionally interacts with KCNH2 leading to a stronger current suppression and marked aggravation of long QT syndrome in the patient carrying variants in both proteins.

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Language(s): eng - English
 Dates: 2019-03-122019-03-242019-03-282019-05-14
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: Biochemical and Biophysical Research Communications
  Other : Biochem. Biophys. Res. Commun.
Source Genre: Journal
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Publ. Info: Orlando, Fla. : Academic Press
Pages: - Volume / Issue: 512 (4) Sequence Number: - Start / End Page: 845 - 851 Identifier: ISSN: 0006-291X
CoNE: https://pure.mpg.de/cone/journals/resource/954922652205_1