Copyright © 2007, European Society of Cardiology
A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia
aDepartment of Medicine, Cardiovascular Section, University of Wisconsin-Madison, 600 Highland Ave H6/349, Madison, WI 53792, United States
bInstituto Nacional de Cardioloia "Ignacio Chàvez", Mexico
cInstituto de Investigaciones Biomédicas, UNAM, Instituto Nacional de Ciencias Médicas y Nutrición, SZ, Mexico
dDepartment of Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN, United States
eDepartment of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, United States
fDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, United States
*Corresponding author. Tel.: +1 608 263 9648; fax: +1 608 263 0405. jcm{at}medicine.wisc.edu
Objectives Individual mutations in the SCN5A-encoding cardiac sodium channel 
-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.
Methods and 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.
KEYWORDS Genetics; Arrhythmia; Sick sinus syndrome; Conduction disorder; Ventricular tachycardia; SCN5A; Sodium current; Frame-shift mutation; Nav1.5; Inherited arrhythmia
1 Contributed equally to this study.
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