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(Circulation. 1995;92:2786-2789.)
© 1995 American Heart Association, Inc.

Articles

Congenital Long QT Syndromes

Toward Molecular Dissection of Arrhythmia Substrates

Andrew A. Grace, PhD, MRCP; Kenneth R. Chien, MD, PhD

From the Department of Medicine (A.A.G., K.R.C.), Center for Molecular Genetics (K.R.C.), and the American Heart Association-Bugher Foundation Center for Molecular Biology (A.A.G., K.R.C.), University of California, San Diego, School of Medicine, La Jolla, Calif; the Departments of Medicine and Biochemistry, University of Cambridge, England (A.A.G.); and the Department of Cardiology, Papworth Hospital (A.A.G.), Cambridge, England.

Correspondence to Andrew A. Grace, PhD, MRCP, American Heart Association-Bugher Foundation Center for Molecular Biology, Department of Medicine, 0613-C, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613.

Key Words: editorials • arrhythmia • genetics • molecular biology

	Introduction

 
The last 12 months could be viewed as the annus mirabilis for the molecular delineation of ventricular arrhythmia substrates, analogous to the celebration of the molecular determinants of gating and selectivity of potassium channels in a previous year.¹ In 1991, the first genetic locus (LQT₁) for the congenital long QT syndromes was identified on chromosome 11, and close linkage to the H-ras-1 gene was reported in a landmark article.² Although the candidate gene was mechanistically appealing and was implicated in each of the first 6 families examined,³ no mutations of the H-ras-1 locus were found, and it has been formally excluded as a site of the genetic defect.⁴ Subsequent studies that utilized linkage analysis documented that the disease was genotypically heterogeneous, which is consistent with the complexity of the repolarization process.⁴ In 1994, two further loci, (LQT₂ and LQT₃) were reported on chromosomes 7 and 3, respectively. Currently, the genetic loci for the majority of families have been accounted for,⁵ with linkage not yet achieved in only 3 of 27 lineages studied by the Salt Lake City group.⁶ The scientific pace maintained by that group has been breathtaking, resulting in the characterization of candidate genes at two of the more recently described locations^{6 7} along with powerful evidence that these genes encode sodium and potassium channels.^{6 7 8} Therefore, as has been previously suspected,⁹ the proximal cause of most autosomal dominant long QT syndromes (LQTS) is a sarcolemmal ion channel defect determining repolarization.¹⁰ The details of these . . . [Full Text of this Article]

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