The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype.
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Research Article|
July 24 2014
Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1
Stephen C. Harmer;
Stephen C. Harmer
*William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
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Jagdeep S. Mohal;
Jagdeep S. Mohal
*William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
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Alice A. Royal;
Alice A. Royal
*William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
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William J. McKenna;
William J. McKenna
†Institute of Cardiovascular Science, Heart Hospital, University College London, 16–18 Westmoreland Street, London W1G 8PH, U.K.
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Pier D. Lambiase;
Pier D. Lambiase
†Institute of Cardiovascular Science, Heart Hospital, University College London, 16–18 Westmoreland Street, London W1G 8PH, U.K.
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Andrew Tinker
Andrew Tinker
1
*William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
1To whom correspondence should be addressed (email a.tinker@qmul.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 01 2014
Revision Received:
May 28 2014
Accepted:
June 10 2014
Accepted Manuscript online:
June 10 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 462 (1): 133–142.
Article history
Received:
April 01 2014
Revision Received:
May 28 2014
Accepted:
June 10 2014
Accepted Manuscript online:
June 10 2014
Citation
Stephen C. Harmer, Jagdeep S. Mohal, Alice A. Royal, William J. McKenna, Pier D. Lambiase, Andrew Tinker; Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1. Biochem J 15 August 2014; 462 (1): 133–142. doi: https://doi.org/10.1042/BJ20140425
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