title: Characterization and mechanisms of action of novel NaV1.5 channel mutations associated with Brugada syndrome.
abstract: BACKGROUND
  Brugada syndrome is a heterogeneous heart rhythm disorder characterized by an atypical right bundle block pattern with ST-segment elevation and T-wave inversion in the right precordial leads. Loss-of-function mutations in SCN5A encoding the cardiac sodium channel Na(V)1.5 are associated with Brugada syndrome. We found novel mutations in SCN5A in 2 different families diagnosed with Brugada syndrome and investigated how those affected Na(V)1.5 channel function.
  
  
  RESULTS
  We performed genetic testing of the probands' genomic DNA. After site-directed mutagenesis and transfection, whole-cell currents were recorded for Na(V)1.5 wild type and mutants heterologously expressed in Chinese hamster ovary-K1 cells. Proband 1 had two novel Na(V)1.5 mutations: Na(V)1.5-R811H and Na(V)1.5-R620H. The Na(V)1.5-R811H mutation showed a significant loss of function in peak Na(+) current density and alteration of biophysical kinetic parameters (inactivation and recovery from inactivation), whereas Na(V)1.5-R620H had no significant effect on the current. Proband 2 had a novel Na(V)1.5-S1218I mutation. Na(V)1.5-S1218I had complete loss of function, and 1:1 expression of Na(V)1.5-wild type and Na(V)1.5-S1218I mimicking the heterozygous state revealed a 50% reduction in current compared with wild type, suggesting a functional haploinsufficiency in the patient.
  
  
  CONCLUSIONS
  Na(V)1.5-S1218I and R811H are novel loss-of-function mutations in the SCN5A gene causing Brugada syndrome.
authors: Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Kirstine
authors: K
authors: Calloe
authors: Marwan M
authors: MM
authors: Refaat
authors: Soren
authors: S
authors: Grubb
authors: Julianne
authors: J
authors: Wojciak
authors: Joan
authors: J
authors: Campagna
authors: Nancy Mutsaers
authors: NM
authors: Thomsen
authors: Robert L
authors: RL
authors: Nussbaum
authors: Melvin M
authors: MM
authors: Scheinman
authors: Nicole
authors: N
authors: Schmitt
mesh_terms: D000200:Action Potentials; D000328:Adult; D000818:Animals; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D007700:Kinetics; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human