A Novel HCN4 Mutation, G1097W, Is Associated With Atrioventricular Block

Abstract

938ZHOU J et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jpGenes encoding α-subunits of If channels have 4 members, the hyperpolarization-activated cyclic nucleotide-gated channels 1-4 (termed HCN1-HCN4). 3 HCN1, -2, and -4 are expressed in the heart and brain, and all have 6 transmembrane helices (S1-S6) and a cyclic nucleotide binding domain (cNBD) in the middle of the C-terminus. 3 Similar to other members of voltagegated cation channels, the 4 subunits of the HCN channels most likely form a tetramer. Compared to other HCN isoforms, HCN4 is known to be more abundant in the heart. 7,8 HCN4 mutations are reported to cause familial sick sinus syndrome 9-11 and sporadic cases of sinus nodal dysfunction; 12 however, their relationship with atrioventricular (AV) block remains unknown. We recently identified a novel HCN4 mutation (G1097W) in a Japanese patient with AV block. The functional characterization of reconstituted If channels shows that the HCN4 mutation could predispose to AV nodal dysfunction, which might provide an important insight into the genetic basis for the AV block.he automaticity of heart rhythm is determined by a concerted function of various ion channels, including at least 4 different types of cation channels: 1-4 T-and L-type Ca 2+ channels, K + channels, and the If channels that carries both K + and Na + ions under physiological conditions (relative permeability ratio: PNa/PK=0.2-0.4), 5 thereby producing a reversal potential of approximately -25 mV. If channels flow in an inward depolarizing current in pacemaker cells after the channels are repolarized by the activation of K + channels and they drive the cell membrane potential up to the threshold of Ca 2+ channel activation. The activation of If channels generates the "pacemaker potential" and determines the rate of automaticity in nodal cells. If channel currents are regulated by intracellular cyclic adenosine monophosphate (cAMP) levels. In addition to hyperpolarization, an increase in cAMP accelerates the pacemaker potential rise by shifting the voltage dependence of If channels to a more positive potential. Background: Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation.

Tachycardia-bradycardia syndrome: Electrophysiological mechanisms and future therapeutic approaches (Review)

“…Loss-of-function HCN4 mutations are known to cause atrioventricular (AV) block, long QT syndrome (LQTS), AF, familial TBS and non-compaction cardiomyopathy in addition to sinus bradycardia (76–80). The G1097W HCN4 mutation, which is a loss-of-function mutation resulting in a hyperpolarizing shift of the activation curve and reduced expression levels, demonstrates 4:1 AV block and reflex sinus tachycardia (81). A missense HCN4 mutation was found to lead to impaired trafficking of the channel to the surface membrane, resulting in SSS, long QT and torsade de pointes (82).…”

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death

“…In mice, temporal control of HCN4 deletion with the Cre‐Lox technique results in a reduction of I f density and heart rate disturbances (sinus pauses and bradycardia) . In humans, HCN4 has an important contribution to heart rate, as demonstrated by several reports that HCN4 variants are associated with sick sinus syndrome, sinus tachycardia, sinus bradycardia, atrioventricular block, and other forms of sinus node dysfunction …”

“…8 In humans, HCN4 has an important contribution to heart rate, as demonstrated by several reports that HCN4 variants are associated with sick sinus syndrome, sinus tachycardia, sinus bradycardia, atrioventricular block, and other forms of sinus node dysfunction. [9][10][11][12][13] The role of HCN4 VUS in modifying the risk of SUD is uncertain, especially in light of recent data from the ClinGen consortium and the channelopathy working group. 14 Nevertheless, we cannot even begin to evaluate whether an association exists in the absence of data demonstrating whether HCN4 VUS affect channel function.…”

HCN4, Sinus Bradycardia and Atrial Fibrillation

“…Interestingly, a similar conclusion was suggested by experiments showing that block of the funny current generates a larger response in AVN than in SAN myocytes. 39 In the study of Zhou et al, 36 a single patient with complete AV block, but no sinus node dysfunction, who had undergone pacemaker implantation, was found to carry the HCN4 mutation G1097W. This was shown to be a loss-of-function mutation associated with a negative shift of the activation curve and a lower membrane expression level.…”

“…In most cases these disorders appear in addition to bradycardia, except with P257S, associated with early onset AF, 35 and G1097W, associated with complete AV block. 36 It is interesting to note that two recent reports 29,30 provide evidence that dysfunctional HCN4 channel mutations can also be linked to cardiac structural abnormalities and specifically to non-compaction cardiomyopathy (NCCM), a disease characterised by non-compacted ventricular myocardial layer with excessive trabeculations, often associated with heart failure, arrhythmias and systemic embolic events.…”