title: A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia.
abstract: OBJECTIVE
  Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance.
  
  
  RESULTS
  A 12-year-old male with congenital sick sinus syndrome (SSS), cardiac conduction disorder (CCD), and recurrent monomorphic ventricular tachycardia (VT) had mutational analysis that identified a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of SCN5A. The mutation was also present in six asymptomatic family members only two of which showed mild ECG phenotypes. The deletion caused a frame-shift mutation (L1821fs/10) with truncation of the C-terminus after 10 missense amino acid substitutions. When expressed in HEK-293 cells for patch-clamp study, the current density of L1821fs/10 was reduced by 90% compared with WT. In addition, gating kinetic analysis showed a 5-mV positive shift in activation, a 12-mV negative shift of inactivation and enhanced intermediate inactivation, all of which would tend to reduce peak and early sodium current. Late sodium current, however, was increased in the mutated channels.
  
  
  CONCLUSIONS
  The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.
authors: Department of Medicine, Cardiovascular Section, University of Wisconsin-Madison, 600 Highland Ave H6/349, Madison, WI 53792, USA.
authors: Bi-Hua
authors: BH
authors: Tan
authors: Pedro
authors: P
authors: Iturralde-Torres
authors: Argelia
authors: A
authors: Medeiros-Domingo
authors: Santiago
authors: S
authors: Nava
authors: David J
authors: DJ
authors: Tester
authors: Carmen R
authors: CR
authors: Valdivia
authors: Teresa
authors: T
authors: Tusié-Luna
authors: Michael J
authors: MJ
authors: Ackerman
authors: Jonathan C
authors: JC
authors: Makielski
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004562:Electrocardiography; D016368:Frameshift Mutation / Q000235:genetics*; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D019683:Penetrance; D010641:Phenotype; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000503:physiopathology
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels