HCN4 Mutations in Multiple Families With Bradycardia and Left Ventricular Noncompaction Cardiomyopathy

Milano, Annalisa; Vermeer, Alexa M.C.; Lodder, Elisabeth M.; Barc, Julien; Verkerk, Arie O.; Postma, Alex V.; Bilt, Ivo A.C. van der; Baars, Marieke J.H.; Haelst, Paul L. van; Çalışkan, Kadir; Hoedemaekers, Yvonne M.; Scouarnec, Solena Le; Redon, Richard; Pinto, Yigal M.; Christiaans, Imke; Wilde, Arthur A.M.; Bezzina, Connie R.

doi:10.1016/j.jacc.2014.05.045

Cited by 171 publications

(165 citation statements)

References 55 publications

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“…22 Variants in other primary arrhythmia genes such as HCN4 and RYR2 23,24 have also been reported in association with LVNC. Excitation-contraction coupling, the fundamental myocardial process of electric stimulation triggering mechanical force generation, by definition implies a tight link between ion channels and sarcomeric contraction.…”

Section: Possible Link To Arrhythmia?mentioning

confidence: 98%

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Rhee

Grove

Ashley

2017

Circ Cardiovasc Genet

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Section: Possible Link To Arrhythmia?mentioning

confidence: 98%

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Rhee

Grove

Ashley

2017

Circ Cardiovasc Genet

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“…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.…”

mentioning

confidence: 89%

“…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. 30 In both cases, however, the changes lead to loss of function and are compatible with the bradycardic phenotype.…”

mentioning

confidence: 89%

“…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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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HCN4, Sinus Bradycardia and Atrial Fibrillation

DiFrancesco¹

2015

Arrhythmia &Amp; Electrophysiology Review

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Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/ hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation.Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.

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Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

Liu

Zhang

Zarrei

et al. 2020

American J of Med Genetics Pt B

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Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58-Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A-B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650-kb interval (LCR15q24B-D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region. K E Y W O R D S15q24 microdeletion, autism spectrum disorder, critical region, de novo

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HCN4 Mutations in Multiple Families With Bradycardia and Left Ventricular Noncompaction Cardiomyopathy

Abstract: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.

Cited by 171 publications

References 55 publications

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

HCN4, Sinus Bradycardia and Atrial Fibrillation

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

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