title: New KCNQ1 mutations leading to haploinsufficiency in a general population; Defective trafficking of a KvLQT1 mutant.
abstract: OBJECTIVE
  KCNQ1 mutations lead to the long QT syndrome (LQTS), characterized by a prolonged QT interval, syncopes and sudden death. However, some mutations are associated with non-penetrant phenotype (no symptoms, QTc normal or borderline). The objective of this study was to determine whether KCNQ1 variants are associated with borderline QTc prolongation in a general population and to evaluate the frequency of carriers.
  
  
  METHODS
  We selected 2008 unrelated and untreated healthy individuals from a non-patient population. The KCNQ1 gene was screened by denaturing high-performance liquid chromatography (dHPLC) in 50 men and 50 women presenting the longest QTc intervals (403 to 443 ms).
  
  
  RESULTS
  We identified a nonsense mutation, Y148X, and an in-frame deletion of the serine residue 276 (DeltaS276), in S2 and S5 transmembrane domains, respectively. DeltaS276 KvLQT1 channels expressed in COS-7 cells failed to conduct any K+ current in the homozygous state. Besides, a slight reduction in channel activity was observed when coexpressed with WT KvLQT1 and IsK. Confocal microscopy performed on transfected COS-7 cells revealed that DeltaS276 KvLQT1 was retained in the endoplasmic reticulum, whereas WT KvLQT1 was localized in the cell membrane. The two mutation carriers presented borderline QTc interval prolongation at slow heart rate but a 24-h ECG recording revealed a marked QTc prolongation at higher heart rate for the Y148X carrier.
  
  
  CONCLUSIONS
  In this population, two subjects with borderline QTc prolongations (438 and 443 ms) were carriers of KCNQ1 mutations leading to haploinsufficiency and are potentially at risk of developing drug-induced arrhythmia. The study provides the first demonstration of a defective cell surface localization of a KvLQT1 mutant missing one amino acid in a transmembrane domain.
authors.affiliation: INSERM U582, Institut de Myologie, IFR no. 14, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris Cedex 13, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gouas
authors.forename: Chloe
authors.initials: C
authors.lastname: Bellocq
authors.forename: Myriam
authors.initials: M
authors.lastname: Berthet
authors.forename: Franck
authors.initials: F
authors.lastname: Potet
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Anne
authors.initials: A
authors.lastname: Forhan
authors.forename: Rachel
authors.initials: R
authors.lastname: Lescasse
authors.forename: Françoise
authors.initials: F
authors.lastname: Simon
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Bernard
authors.initials: B
authors.lastname: Hainque
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baró
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D018389:Codon, Nonsense; D005260:Female; D017353:Gene Deletion; D006239:Haplotypes; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated