title: Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function.
abstract: BACKGROUND
  Two genetic variants in SCN5A, encoding the Nav1.5 Na+channel α-subunit, were found in a 5-month-old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C-terminal truncation (R1944Δ).
  
  
  RESULTS
  To investigate their functional relevance with patch clamp experiments in transfected HEK-293 cells. The Q1832E mutation drastically reduced Nav1.5 current density. The R1944Δ C-terminal truncation had negligible effects on Nav1.5 current density. Neither of the mutations affected the voltage dependence of steady activation and inactivation or influenced the late Na+current or the recovery from inactivation. Biochemical and immunofluorescent approaches demonstrated that the Q1832E mutation caused severe trafficking defects. Polymerase chain reaction cloning and sequencing the victim's genomic DNA allowed us to determine that the two variants were in trans. We investigated the functional consequences by coexpressing Nav1.5(Q1832E) and Nav1.5(R1944Δ), which led to a significantly reduced current amplitude relative to wild-type.
  
  
  CONCLUSIONS
  These sudden infant death syndrome (SIDS)-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.
authors.affiliation: Pediatrics, NYU School of Medicine, New York, NY.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gando
authors.affiliation: Pediatrics, NYU School of Medicine, New York, NY.
authors.forename: Jace
authors.initials: J
authors.lastname: Morganstein
authors.affiliation: Pediatrics, NYU School of Medicine, New York, NY.
authors.forename: Kundan
authors.initials: K
authors.lastname: Jana
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: McDonald
authors.affiliation: Molecular Genetics Laboratory, Office of Chief Medical Examiner, New York, NY.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Pediatrics, NYU School of Medicine, New York, NY.|Physiology & Neuroscience, NYU School of Medicine, New York, NY.|Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY.
authors.forename: William A
authors.identifier: http://orcid.org/0000-0003-1522-8326
authors.initials: WA
authors.lastname: Coetzee
mesh_terms: D016757:Death, Sudden, Cardiac; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015994:Incidence; D007223:Infant; D015640:Ion Channel Gating / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012964:Sodium / Q000378:metabolism*; D013398:Sudden Infant Death / Q000235:genetics*; D015996:Survival Rate
chemical_list: D005819:Genetic Markers; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D012964:Sodium
keywords: Brugada syndrome; Na+ Channels; channelopathies; sudden infant death syndrome