Abstract
Objectives. The aim of this review was to develop a hypothesis for the molecular pathophysiology of the inherited long QT syndrome.Background. The pathophysiology of the long QT syndrome is unknown. An abnormality of the sympathetic nervous system has been suspected because of the slow heart rates observed and the common precipitation of syncope by adrenergic stimulation (exercise or fright), The characteristic QT prolongation and torsade de pointes arrhythmias suggest a potassium ion (K+) abnormality. Recent findings from molecular biology and genetic linkage analysis studies provide a basis for a new hypothesis that unifies these clinical manifestations.Methods. Several recent studies regarding rasproteins were evaluated and correlated. Associations between rasproteins, G protein function and the known features of the long QT syndrome were identified. Based on these associations, a hypothesis for the molecular pathophysiology was developed.Results. The Romano-Ward long QT phenotype is linked to the Harvey ras-1 gene on chromosome 11 in many, but not all, families. Rasgenes exhibit G protein properties, acting as intermediaries in transmembrane signaling pathways including K+and beta-adrenergtc channels. Mutation of rasp21 protein significantly reduces the G protein function of the rasprotein, thereby interfering with signal transduction.Conclusions. These various studies suggest that a mutation of the disease gene (not necessarily H-ras-1) alters the G protein function of the gene and interferes with delayed rectifier K+and beta-receptor channel signaling. This hypothesis appears to explain and unify the several characteristic features of the long QT syndrome.
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