Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular arrhythmias. Recently, the applicant has demonstrated that mutations in KVLQT1, hERG, and SCN5A cause the autosomal dominant forms of this disorder. The long-term goals of the work proposed in this application are to define the molecular and cellular mechanisms of LQT.
The first aim of the proposal is to define the function of KVLQT1 and the functional consequences of LQT-associated mutations in this gene. The biophysical and pharmacological properties of KVLQT1 channels will be determined by heterologous expression in Xenopus oocytes using two microelectrode voltage-clamp techniques. Site directed mutagenesis will be used to introduce LQT-associated mutations into KVLQT1. The physiologic consequences of these mutations will be defined by coexpressing mutant and wild-type KVLQT1 channels.
The second aim i s to define and characterize homologues of KVLQT1 and hERG. Preliminary data indicate the homologues exist for each gene. These homologues will be characterized using cDNA sequence analyses and genomic localization studies. The genetic linkage and mutation analyses will be used to determine if mutations in these genes also cause long QT. Finally, the physiologic characteristics of these homologues will be determined by expression in Xenopus oocytes.
The third aim i s to identify and characterize genes responsible for autosomal recessive, syndactyly-associated, and acquired long QT. The long QT genes will be identified using candidate gene and positional cloning-candidate gene approaches. The physiologic consequences of mutations in these LQT genes will be defined by expression in Xenopus oocytes.
The fourth aim i s to enable genetic diagnosis and prognosis with long QT. The applicant will define the genomic structure for long QT genes, characterize the spectrum of long QT causing mutations, and complete genotype/phenotype analyses for each gene. This information will be used to develop sensitive and specific genetic tests.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL046401-07
Application #
2028608
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1992-05-01
Project End
2002-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Mohler, Peter J; Splawski, Igor; Napolitano, Carlo et al. (2004) A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A 101:9137-42
Zhang, Li; Vincent, G Michael; Baralle, Marco et al. (2004) An intronic mutation causes long QT syndrome. J Am Coll Cardiol 44:1283-91
Abbott, G W; Sesti, F; Splawski, I et al. (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175-87
Keating, M T (1996) The long QT syndrome. A review of recent molecular genetic and physiologic discoveries. Medicine (Baltimore) 75:1-5
Keating, M T (1995) Genetic approaches to cardiovascular disease. Supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. Circulation 92:142-7