The Symptom Complex of Familial Sinus Node Dysfunction and Myocardial Noncompaction Is Associated With Mutations in the HCN4 Channel

Abstract

The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.

HCN4, Sinus Bradycardia and Atrial Fibrillation

“…The same combined phenotype is also reported in a family, previously investigated by the same group, carrying the HCN4-695X mutation, and in a single patient with a mutation in the terminal part of the C-terminus (P883R), though in this case no functional study is provided. 30 These findings confirm the notion that, as well as controlling pacemaker activity, HCN4 channels contribute to normal cardiac development. 37 Since HCN4 is expressed in cardiac progenitor cells, as a potential underlying mechanism, the authors suggest the possibility that dysfunctional HCN4 mutations directly disrupt the normal ventricular compaction process during development.…”

“…37 Since HCN4 is expressed in cardiac progenitor cells, as a potential underlying mechanism, the authors suggest the possibility that dysfunctional HCN4 mutations directly disrupt the normal ventricular compaction process during development. 29,30 The G482R mutation was found in combination with a common variant (CSRP3-W4R) in one study 30 but not in another, 29 suggesting that the variant is not essential, though it can act as a predisposing condition. Expression of heterozygous wild-type/G482R mutated channels generated apparently contrasting results in the two studies: a strong negative shift of the activation curve in one study 29 and a reduced membrane expression with no shift of the activation curve in the other.…”

“…27,28 • Recently reported loss-of-function mutations 29,30 have been proposed to cause a symptom complex comprising bradycardia and ventricular structural abnormalities (non-compaction cardiomyopathy).…”

“…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.…”

Letter by Barison et al Regarding Article, “Familial Clustering of Mitral Valve Prolapse in the Community”

“…Nevertheless, previous studies correlated MVP to other morphological abnormalities, involving papillary muscles, 2 the right ventricle, and the tricuspid valve, 3 and to electrophysiological disorders, such as ion-channel diseases, 4 supraventricular and ventricular arrhythmias, and sudden death. 5 In particular, it has been hypothesized that the same genes may control the myocardial, valvular, and conduction system formation during early embryonic heart development, 4 explaining why several different pathological phenotypes are often associated. Other pathological and cardiovascular magnetic resonance studies have described perivalvular ventricular fibrosis and papillary muscle fibrosis, 2 suggesting that MVP might be an acquired disease progressing over time owing to a tight relationship between the prolapsing valve and ventricular structure, with possible myocardial remodeling and enhanced arrhythmic susceptibility.…”