title: New mutations in the KVLQT1 potassium channel that cause long-QT syndrome.
abstract: BACKGROUND
  Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A).
  
  
  RESULTS
  After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein.
  
  
  CONCLUSIONS
  We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.
authors.affiliation: Lillie Frank Abercrombie Section of Cardiology, Department of Pediatrics, Baylor College of Medicine, Houston, Tex 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: A J
authors.initials: AJ
authors.lastname: Moss
authors.forename: J
authors.initials: J
authors.lastname: Robinson
authors.forename: V
authors.initials: V
authors.lastname: Goytia
authors.forename: J C
authors.initials: JC
authors.lastname: Perry
authors.forename: G M
authors.initials: GM
authors.lastname: Vincent
authors.forename: S G
authors.initials: SG
authors.lastname: Priori
authors.forename: M H
authors.initials: MH
authors.lastname: Lehmann
authors.forename: S W
authors.initials: SW
authors.lastname: Denfield
authors.forename: D
authors.initials: D
authors.lastname: Duff
authors.forename: S
authors.initials: S
authors.lastname: Kaine
authors.forename: W
authors.initials: W
authors.lastname: Shimizu
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D016022:Case-Control Studies; D004274:DNA, Recombinant; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*
chemical_list: D004274:DNA, Recombinant; D015221:Potassium Channels