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

Matteo Vatta, Robert Dumaine, George Varghese, Todd A. Richard, Wataru Shimizu, Naohiko Aihara, Koonlawee Nademanee, Ramon Brugada, Josep Brugada, Gumpanart Veerakul, Hua Li, Neil E. Bowles, Pedro Brugada, Charles Antzelevitch, Jeffrey Towbin

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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 (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.

Original languageEnglish (US)
Pages (from-to)337-345
Number of pages9
JournalHuman molecular genetics
Volume11
Issue number3
StatePublished - Feb 1 2002

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Brugada Syndrome
Mutation
Sodium Channels
Nucleic Acid Conformation
Long QT Syndrome
Southeastern Asia
Ventricular Fibrillation
Sudden Death
Xenopus
DNA Sequence Analysis
Ion Channels
Genes
Action Potentials
Oocytes
Electrocardiography
Alleles
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. / Vatta, Matteo; Dumaine, Robert; Varghese, George; Richard, Todd A.; Shimizu, Wataru; Aihara, Naohiko; Nademanee, Koonlawee; Brugada, Ramon; Brugada, Josep; Veerakul, Gumpanart; Li, Hua; Bowles, Neil E.; Brugada, Pedro; Antzelevitch, Charles; Towbin, Jeffrey.

In: Human molecular genetics, Vol. 11, No. 3, 01.02.2002, p. 337-345.

Research output: Contribution to journalArticle

Vatta, M, Dumaine, R, Varghese, G, Richard, TA, Shimizu, W, Aihara, N, Nademanee, K, Brugada, R, Brugada, J, Veerakul, G, Li, H, Bowles, NE, Brugada, P, Antzelevitch, C & Towbin, J 2002, 'Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome', Human molecular genetics, vol. 11, no. 3, pp. 337-345.
Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Human molecular genetics. 2002 Feb 1;11(3):337-345.
Vatta, Matteo ; Dumaine, Robert ; Varghese, George ; Richard, Todd A. ; Shimizu, Wataru ; Aihara, Naohiko ; Nademanee, Koonlawee ; Brugada, Ramon ; Brugada, Josep ; Veerakul, Gumpanart ; Li, Hua ; Bowles, Neil E. ; Brugada, Pedro ; Antzelevitch, Charles ; Towbin, Jeffrey. / Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. In: Human molecular genetics. 2002 ; Vol. 11, No. 3. pp. 337-345.
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AU - Dumaine, Robert

AU - Varghese, George

AU - Richard, Todd A.

AU - Shimizu, Wataru

AU - Aihara, Naohiko

AU - Nademanee, Koonlawee

AU - Brugada, Ramon

AU - Brugada, Josep

AU - Veerakul, Gumpanart

AU - Li, Hua

AU - Bowles, Neil E.

AU - Brugada, Pedro

AU - Antzelevitch, Charles

AU - Towbin, Jeffrey

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N2 - 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.

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