Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)
D. Woodrow Benson, Dao W. Wang, Macaira Dyment, Timothy K. Knilans, Frank A. Fish, Margaret J. Strieper, Thomas H. Rhodes, Alfred L. George Jr.
D. Woodrow Benson, Dao W. Wang, Macaira Dyment, Timothy K. Knilans, Frank A. Fish, Margaret J. Strieper, Thomas H. Rhodes, Alfred L. George Jr.
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Article Genetics

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Abstract

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.

Authors

D. Woodrow Benson, Dao W. Wang, Macaira Dyment, Timothy K. Knilans, Frank A. Fish, Margaret J. Strieper, Thomas H. Rhodes, Alfred L. George Jr.

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Biophysical properties of R1632H. (a) Comparison of current-voltage rela...
Biophysical properties of R1632H. (a) Comparison of current-voltage relationship for WT-hH1 (open circles) and R1632H (filled circles, n = 25). Current is normalized to cell capacitance to give a measure of sodium current density. There is no difference in current density between WT-hH1 and R1632H at all tested voltages. (b) Voltage dependence of fast inactivation time constants for WT-hH1 (open circles) and R1632H (filled circles, n = 25). Differences between WT-hH1 and mutant channel were significant for τ1 (P < 0.0001) and τ2 (P < 0.05) at voltages between –60 to +50 mV. (c) Voltage dependence of sodium channel availability and activation (symbol definitions are shown as an inset, and their shading patterns are explained in the y-axis labels). Voltage dependence of sodium channel availability (steady-state inactivation) was obtained using a two-pulse protocol as illustrated by the inset. The membrane potentials for half-maximal inactivation and slope factors are provided in Table 2. The activation curve was constructed as described in the legend of Figure 5, and parameters are given in Table 2. (d) Time course of recovery from inactivation at –120mV (–140 mV for R1632H). The time constants and fractional amplitudes (given in parentheses) are provided in Table 2.