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Human Molecular Genetics, 2002, Vol. 11, No. 3 337-345
© 2002 Oxford University Press

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

Matteo Vatta1, Robert Dumaine4, George Varghese1, Todd A. Richard4, Wataru Shimizu5, Naohiko Aihara5, Koonlawee Nademanee6, Ramon Brugada2, Josep Brugada7, Gumpanart Veerakul9, Hua Li1, Neil E. Bowles1, Pedro Brugada8, Charles Antzelevitch4 and Jeffrey A. Towbin1,3,+

1Department of Pediatrics (Cardiology), 2Department of Medicine (Cardiology) and 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, 4Masonic Medical Research Laboratory, Utica, NY, USA, 5Department of Internal Medicine (Cardiology), National Cardiovascular Center, Osaka, Japan, 6Department of Medicine (Cardiology), University of Southern California, Los Angeles, CA, USA, 7Cardiovascular Institute, Hospital Clinic, University of Barcelona, Spain, 8Cardiovascular Center, OLV Hospital, Aalst, Belgium and 9Department of Cardiology, Bhumibol Adulyadej Hospital, RTAF, Bangkok, Thailand

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 (INa) 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.

+ To whom correspondence should be addressed at: Pediatric Cardiology, Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030, USA. Tel: +1 713 798 7342; Fax: +1 713 798 8085; Email: jtowbin@bcm.tmc.edu


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