title: Functional effects of mutations in KvLQT1 that cause long QT syndrome.
abstract: BACKGROUND
  The long QT syndrome (LQT) is caused by mutations in genes encoding ion channels that modulate the duration of ventricular action potentials. One of these genes, KVLQT1, encodes an alpha subunit that coassembles with another subunit, hminK, to form the cardiac slow delayed rectifier (I(Ks)) K+ channel.
  
  
  RESULTS
  The functional effects of seven mutations in KVLQT1 were assessed using two-microelectrode voltage clamp and the Xenopus oocyte expression system. Most mutations in KVLQT1 caused loss of function when expressed alone. Oocytes were also injected with equal amounts of wild-type (WT) KVLQT1 and mutant KVLQT1 cRNA (with or without coinjection of hminK) and the resulting currents compared to currents induced by WT KvLQT1 alone. A341V, R190Q, or G189R KVLQT1 subunits did not affect expression of WT KvLQT1. The other mutations in KVLQT1 caused a variable degree of dominant-negative suppression of I(Ks). The order of potency for this effect was G345E > G306R = V254M > A341E.
  
  
  CONCLUSIONS
  LQT1-associated mutations in KVLQT1 caused a spectrum of dysfunction in I(Ks) and KvLQT1 channels. The degree of I(Ks) dysfunction did not correlate with the QTc interval or the presence of symptoms in the respective gene carriers. In contrast to previous reports, we found that loss of function mutations are not exclusive to recessively inherited LQT.
authors.affiliation: University of Utah, the Department of Medicine, Salt Lake City 84112-5330, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000818:Animals; D005260:Female; D005838:Genotype; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D014981:Xenopus
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated