title: Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1.
abstract: 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.
authors.affiliation: *William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harmer
authors.affiliation: *William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
authors.forename: Jagdeep S
authors.initials: JS
authors.lastname: Mohal
authors.affiliation: *William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Royal
authors.affiliation: †Institute of Cardiovascular Science, Heart Hospital, University College London, 16-18 Westmoreland Street, London W1G 8PH, U.K.
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.affiliation: †Institute of Cardiovascular Science, Heart Hospital, University College London, 16-18 Westmoreland Street, London W1G 8PH, U.K.
authors.forename: Pier D
authors.initials: PD
authors.lastname: Lambiase
authors.affiliation: *William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D016466:CHO Cells; D003412:Cricetulus; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000502:physiology; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated