title: Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A.
abstract: BACKGROUND
  Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains.
  
  
  OBJECTIVE
  This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias.
  
  
  METHODS
  A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed.
  
  
  RESULTS
  The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not.
  
  
  CONCLUSIONS
  A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing Na(V)1.5 channels in vitro.
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Tan
authors.forename: Pedro
authors.initials: P
authors.lastname: Iturralde-Torres
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusié-Luna
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000704:Analysis of Variance; D053840:Brugada Syndrome / Q000235:genetics*; D017809:Fatal Outcome; D005334:Fever / Q000150:complications; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels