title: Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome.
abstract: BACKGROUND
  Loss-of-function mutations in SCN5A have been associated with the Brugada syndrome. We report the first Brugada syndrome family with compound heterozygous mutations in SCN5A. The proband inherited 1 mutation from each parent and transmitted 1 to each daughter.
  
  
  RESULTS
  The effects of the mutations on the function of the sodium channel were evaluated with heterologous expression in TSA201 cells, patch-clamp study, and confocal microscopy. Genetic analysis revealed that the proband carried 2 heterozygous missense mutations (P336L and I1660V) on separate alleles. He displayed a coved-type ST-segment elevation and a prolonged PR interval (280 ms). One daughter inherited P336L and exhibited a prolonged PR (210 ms). The other daughter inherited mutation I1660V and displayed a normal PR interval. Both daughters had a slightly elevated, upsloping ST-segment elevation. The parents had normal ECGs. Patch-clamp analysis showed that the P336L mutation reduced I(Na) by 85% relative to wild type. The I1660V mutation produced little measurable current, which was rescued by room temperature incubation for 48 hours. Sodium channel blockers also rescued the I1660V current, with mexiletine proving to be the most effective. Confocal immunofluorescence showed that I1660V channels conjugated to green fluorescent protein remained trapped in intracellular organelles.
  
  
  CONCLUSIONS
  Mutation P336L produced a reduction in cardiac I(Na), whereas I1660V abolished it. Only the proband carrying both mutations displayed the Brugada syndrome phenotype, whereas neither mutation alone produced the clinical phenotype. I1660V channels could be rescued pharmacologically and by incubation at room temperature. The present data highlight the role of compound heterozygosity in modulating the phenotypic expression and penetrance of Brugada syndrome.
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. jcordeiro@mmrl.edu
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Kui
authors.initials: K
authors.lastname: Hong
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Orsino
authors.forename: Yue Sheng
authors.initials: YS
authors.lastname: Wu
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006580:Genetic Carrier Screening; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D011392:Proline / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D007532:Isoleucine; D011392:Proline; D007930:Leucine; D014633:Valine