TY - JOUR
T1 - A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia
AU - Tan, Bi Hua
AU - Iturralde-Torres, Pedro
AU - Medeiros-Domingo, Argelia
AU - Nava, Santiago
AU - Tester, David J.
AU - Valdivia, Carmen R.
AU - Tusié-Luna, Teresa
AU - Ackerman, Michael J.
AU - Makielski, Jonathan C.
N1 - Funding Information:
This work was supported by an American Heart Association (AHA), Greater Midwest Affiliate Postdoctoral Fellowship to BH.T., AHA Established Investigator Award to M.J.A., and NIH grant HD42569 to M.J.A and HL71092 to J.C.M.. We are particularly indebted to family members for their participation in this study.
PY - 2007/12/1
Y1 - 2007/12/1
N2 - Objectives: Individual mutations in the SCN5A-encoding cardiac sodium channel α-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.
AB - Objectives: Individual mutations in the SCN5A-encoding cardiac sodium channel α-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.
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U2 - 10.1016/j.cardiores.2007.08.006
DO - 10.1016/j.cardiores.2007.08.006
M3 - Article
C2 - 17897635
AN - SCOPUS:35548941783
SN - 0008-6363
VL - 76
SP - 409
EP - 417
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 3
ER -