Familial Sinus Bradycardia Associated with a Mutation in the Cardiac Pacemaker Channel

Milanesi, Raffaella; Baruscotti, Mirko; Gnecchi‐Ruscone, Tomaso; DiFrancesco, Dario

doi:10.1056/nejmoa052475

Cited by 358 publications

(301 citation statements)

References 23 publications

Supporting

Mentioning

277

Contrasting

Unclassified

Order By: Relevance

“…4). To further confirm this finding we extended our analyses and investigated additional marker genes for the conduction system also by qPCR, namely Shox2, Tbx3, and Cx30.2 (Coppen et al, 1998;Hoogaars et al, 2004;Kreuzberg et al, 2005;Milanesi et al, 2006;Mommersteeg et al, 2007;Espinoza-Lewis et al, 2009). All marker genes were strongly up-regulated in Tbx5-overexpressing cells, except Cx30.2 (Figs.…”

Section: Tbx5 Overexpression In Murine Es Cells and Xenopus 2637mentioning

confidence: 62%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

View full text Add to dashboard Cite

The T-box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi-quantitative and quantitative RT-PCR analyses, we observed an up-regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down-regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased.

show abstract

Section: Tbx5 Overexpression In Murine Es Cells and Xenopus 2637mentioning

confidence: 62%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

View full text Add to dashboard Cite

show abstract

“…38 Mutations in HCN4 have been associated with sinus node dysfunction. 39,40 The SNP rs10824026 is located on chromosome 10q22, 5-kb upstream of SYNPO2L. 18 Beqqali et al 41 identified the gene as encoding a cytoskeletal protein, which is highly expressed in the Z-disc of cardiac and skeletal muscle.…”

Section: The 4q25 Locusmentioning

confidence: 99%

Atrial fibrillation: the role of common and rare genetic variants

Olesen

Nielsen

Haunsø³

et al. 2013

Eur J Hum Genet

102

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1-2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain-and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.

show abstract

“…In particular, the role of HCN channels as the dominant mechanism in heart rate regulation has repeatedly been called into question (4,23). Human genetic studies have suggested that HCN4 channels are important components of the SAN pacemaker machinery (9)(10)(11)(12). A contribution of I f to heart rate determination is further supported by the observation of a heart rate-lowering effect in both humans and rodents when I f is specifically blocked with IVA (13,14,24).…”

Section: Hhcn4 -573x Expression Eliminates Camp Sensitivity Of If Andmentioning

confidence: 99%

“…Although these biophysical properties seem to make f-channels ideal molecular targets for heart rate regulation, the contribution of the major I f -mediating cardiac isoforms HCN2 and HCN4 to SAN function remains highly controversial. Although human genetic (9)(10)(11)(12) and pharmacologic (5,13,14) studies suggest a significant role for HCN4 subunits in SAN pacemaking in humans and rodents, recent data from transgenic mouse models have challenged this view (15,16). Targeted deletion of HCN4 in adult mice was found to cause heart ratedependent sinus pauses but to have no effect on either basal or maximal heart rate or heart rate regulation (16).…”

mentioning

confidence: 99%

Control of heart rate by cAMP sensitivity of HCN channels

Alig

Marger

Mesirca

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

114

View full text Add to dashboard Cite

''Pacemaker'' f-channels mediating the hyperpolarization-activated nonselective cation current I f are directly regulated by cAMP. Accordingly, the activity of f-channels increases when cellular cAMP levels are elevated (e.g., during sympathetic stimulation) and decreases when they are reduced (e.g., during vagal stimulation). Although these biophysical properties seem to make f-channels ideal molecular targets for heart rate regulation by the autonomic nervous system, the exact contribution of the major I f-mediating cardiac isoforms HCN2 and HCN4 to sinoatrial node (SAN) function remains highly controversial. To directly investigate the role of cAMP-dependent regulation of hyperpolarization activated cyclic nucleotide activated (HCN) channels in SAN activity, we generated mice with heart-specific and inducible expression of a human HCN4 mutation (573X) that abolishes the cAMP-dependent regulation of HCN channels. We found that hHCN4 -573X expression causes elimination of the cAMP sensitivity of I f and decreases the maximum firing rates of SAN pacemaker cells. In conscious mice, hHCN4 -573X expression leads to a marked reduction in heart rate at rest and during exercise. Despite the complete loss of cAMP sensitivity of If, the relative extent of SAN cell frequency and heart rate regulation are preserved. Our data demonstrate that cAMPmediated regulation of If determines basal and maximal heart rates but does not play an indispensable role in heart rate adaptation during physical activity. Our data also reveal the pathophysiologic mechanism of hHCN4 -573X-linked SAN dysfunction in humans.bradycardia ͉ hyperpolarization cyclic nucleotide-gated ion channels ͉ pacemaker activity ͉ sinoatrial node ͉ transgenic mice H eart automaticity is a fundamental physiological function in higher organisms. The dominant pacemaker of mammalian hearts is the sinoatrial node (SAN). Dysfunction or failure of SAN activity in humans may lead to an abnormally low heart rate, causing such symptoms as palpitations, fatigue, and syncope, which eventually require implantation of a pacemaker device (1). Elevated resting heart rate, in contrast, is associated with increased cardiovascular mortality and morbidity (2, 3). Despite the importance of cardiac pacemaking as a physiological process, the complex mechanisms underlying SAN automaticity and heart rate regulation remain incompletely understood. SAN activity is controlled by the autonomic nervous system; cholinergic and ␤-adrenergic stimulation either slows or accelerates spontaneous SAN activity. Several ionic currents contribute to cardiac automaticity (4-6). Some of these currents are targets of regulation by the autonomic nervous system, but their physiological importance is a matter of debate (4, 5). ''Pacemaker'' f-channels mediating the hyperpolarizationactivated nonselective cation current I f , in particular, are directly regulated by cAMP (7). These channels are homotetrameric or heterotetrameric complexes of hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits (8...

show abstract

Familial Sinus Bradycardia Associated with a Mutation in the Cardiac Pacemaker Channel

Cited by 358 publications

References 23 publications

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Atrial fibrillation: the role of common and rare genetic variants

Control of heart rate by cAMP sensitivity of HCN channels

Contact Info

Product

Resources

About