Mutations of the human cardiac Na+
channel gene (SCN5A
) underlie multiple cardiac diseases, including long QT syndrome and Brugada syndrome. While most of the mutations that cause long QT syndrome result in a gain of Na+
channel function, mutations that cause Brugada syndrome invariably result in a loss of Na+
channel function. Recent studies have identified yet another class of mutations in the Na+
channel that cause isolated conduction disease. Tan et al. (3
) provided the first evidence that a mutation in SCN5A
causes competing shifts in activation and inactivation gating, where the net effect is a small reduction in Na+
current — sufficient to cause conduction slowing, but not Brugada syndrome. While this suggests that manifestation of a particular rhythm phenotype (Brugada syndrome or conduction defect) may depend on the interplay between competing gating lesions, it is also likely that other, unrecognized factors contribute to manifestation of a particular disease phenotype. Recent studies have identified a novel gene locus for Brugada syndrome (10
) on chromosome 3p22-25, distinct from the known Na+
channel loci and overlapping with a previously reported condition arising from locus 3p22-25 — dilated cardiomyopathy with conduction disease (22
). Although the functional role of this gene locus has not been identified, the study suggests that other as yet unidentified genes could play a role in the manifestation of disorders in cardiac excitability.
We identified a novel mutation, T512I, in the Na+ channel gene of a 2-year-old boy diagnosed with second-degree AV conduction block. The T512I mutation, when heterologously expressed, caused hyperpolarizing shifts in activation and inactivation, and also enhanced slow inactivation. However, the common polymorphism H558R also found in this child’s Na+ channel gene, which had no effect on wild-type Na+ current, attenuated the gating effects caused by mutation T512I. The polymorphism entirely restored the voltage-dependent activation and inactivation voltage shifts caused by the T512I mutation, but only partially restored the kinetic features of slow inactivation. No other family member carried the loss-of-function mutation (T512I) except the mother, who also carried the corrective H558R variant on the same allele (Figure a).
While additional studies will be required to firmly establish causality between conduction block and modest changes in slow inactivation, we offer the following hypotheses for linkage between the biophysical observations and the observed phenotypes. The patient described here exhibits AV conduction slowing (prolonged PR intervals) but no intraventricular or intra-atrial conduction defect (normal P wave and QRS duration). Recent studies have associated similar Na+
channel slow-inactivation gating abnormalities with AV conduction defects in patients not exhibiting evidence of other conduction slowing (9
). These results contrast markedly with the phenotype of another mutation (G514C) associated with slow AV conduction, as well as delayed conduction throughout the atria and ventricles, including broad P waves, PR interval prolongation, and widening of the QRS complex (3
). It is possible that enhanced slow inactivation produced by H558R/T512I, which would cause Na+
channels to recover from inactivation more slowly during diastole than wild-type channels do (Figure a), provides a mechanism whereby AV conduction is slowed in preference to atrial or ventricular conduction. Mutations that preferentially delay recovery from inactivation by enhancing slow inactivation could disproportionately affect cells with longer inherent action potential duration (Purkinje cells). In contrast, as in the case of G514C, mutations targeting the channel activation
process could affect the myocardium more uniformly, as has been observed (3
). Consistent with this idea, it is noteworthy that in the present study H558R entirely eliminated the T512I effect on activation gating (Figure b), but only partly corrected the slow inactivation defect. Greater accumulation of Na+
channel slow inactivation upon successive stimuli in Purkinje cells, with their longer action potential duration and smaller consequent diastolic interval (23
), could lead to greater loss of Na+
channel function in these cells at rapid heart rates (130 beats per minute, basal heart rate in the proband), and thereby produce isolated AV conduction delay. Moreover, a premature stimulus could also further compromise the Purkinje diastolic interval and lead to dramatic loss of Na+
current and result in all-or-none repolarization and conduction block.
In adulthood, the mother’s electrophysiologic phenotype (by history), ECG, and 24-hour ambulatory monitoring was entirely normal. It is possible that the slower heart rate of the mother and consequent longer diastolic interval provides sufficient time for recovery from slow inactivation and thereby did not result in a disease phenotype. While it is unknown whether she displayed ECG abnormalities similar to the proband’s during childhood, reduced penetrance of abnormalities in adults with SCN5A
mutations has been previously described (3
). This may also relate to unidentified factors controlling ion channel function and expression.
There is increasing awareness of the role of common polymorphisms in altering gene function and in susceptibility to disease. Studies have linked gene polymorphisms to elevated risk for cystic fibrosis, Alzheimer disease (12
), and even heart disease (25
). In addition to their role in disease, polymorphisms are also thought to confer sensitivity to drug therapy (27
), as well as proarrhythmic risk from drug therapy (15
). This study provides the first example in which a polymorphism in the same gene as a rare mutation alters the biophysical effect of the mutation on the channel protein.