From Lillie Frank Abercrombie Section of Cardiology, Department of
Pediatrics (H.L, Q.C., V.G., S.W.D., Q.W., J.A.T.), and Department of
Molecular and Human Genetics (J.A.T.), Baylor College of Medicine, Houston,
Tex; Children's Hospital and Health Center, San Diego, Calif (J.C.P.);
Department of Medicine, University of Rochester Medical Center, Rochester, NY
(A.J.M., J.R.); Department of Medicine, LDS Hospital and University of Utah
School of Medicine, Salt Lake City (G.M.V.); Department of Cardiology,
University of Pavia and Policlinico S. Matteo, IFCCS, Pavia, Italy (S.G.P.,
P.J.S.); Arrhythmia Center, Sinai Hospital, Wayne State University School of
Medicine, Detroit, Mich (M.H.L.); Pediatric Cardiology, Our Lady's
Hospital for Sick Children, Dublin, Ireland (D.D.); Pediatric Cardiology,
Children's Mercy Hospital, Kansas City, Mo (S.K.); and National
Cardiovascular Center, Osaka, Japan (W.S.).
Correspondence to Jeffrey A. Towbin, MD, Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030. E-mail jtowbin{at}bcm.tmc.edu
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).
Methods and 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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
New Mutations in the KVLQT1 Potassium Channel That Cause Long-QT Syndrome
Key Words: arrhythmias • long-QT syndrome • potassium • death, sudden • KVLQT1
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