Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome

Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2002; 11(3):337-45.
Source: PubMed


Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5A in three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopus oocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I(Na)) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.

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    • "R1193Q has been implicated in both LQTs type 3, a gain of function disease,16 and in sudden unexplained nocturnal death syndrome, a loss of function disease.17 At the same time, R1193Q is considered as a polymorphism in Asians with an allele frequency of 8%.4,18 "
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    • "In the last decade of the past century, Josep and Pedro Brugada described eight patients with recurrent episodes of aborted sudden death, an electrocardiographic pattern characterized by a right bundle branch block and by a distinct coved-type ST-segment elevation in the right precordial leads V1–V3, but with no signs of structural heart disease [3] [4]. It was only in 2002 that the formerly called ''sudden unexpected nocturnal death syndrome (SUNDS),'' well known in southeast of Asia, was recognized as the same genetic and pathophysiologic condition of the BS [5]. The BS is a ''channellopathy'' typically associated with a high risk for SCD in young and otherwise healthy adults [6], in whom is responsible for 4–12% of all SCD. "
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    • "In general, LQT3 is caused by a gain of channel function while BrS is caused by a loss of channel function [6], [7]. Distinct cardiac phenotypes caused by SCN5A mutations have been described, including atrial fibrillation [8], sick sinus syndrome (SSS), conduction disorders such as atriventricular (AV)-block, and several more complex phenotypes [9]–[11], Dilated cardiomyopathy (DCM) is characterized by dilated cardiac chambers and reduced systolic function, which causes congestive heart failure. Patients with a family history of DCM account for approximately 20 to 25% of idiopathic DCM cases [12], [13]. "
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