title: Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.
abstract: 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.
authors.affiliation: Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.forename: George
authors.initials: G
authors.lastname: Varghese
authors.forename: Todd A
authors.initials: TA
authors.lastname: Richard
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Naohiko
authors.initials: N
authors.lastname: Aihara
authors.forename: Koonlawee
authors.initials: K
authors.lastname: Nademanee
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.forename: Gumpanart
authors.initials: G
authors.lastname: Veerakul
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001208:Asia; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D006801:Humans; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012890:Sleep; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013577:Syndrome; D014982:Xenopus laevis
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels