A Novel PITX2c Gain-of-Function Mutation, p.Met207Val, in Patients With Familial Atrial Fibrillation

Mechakra, Asma; Footz, Tim; Walter, Michael A.; Aránega, Amelia; Hernández-Torres, Francisco; Morel, E.; Millat, Gilles; Yang, Yi‐Qing; Chahine, Mohamed; Chevalier, Philippe; Christé, Georges

doi:10.1016/j.amjcard.2018.11.047

Cited by 17 publications

(32 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These changes could contribute to the long-term stabilization of the arrhythmia by shortening the AP duration (APD) (González de la Fuente et al, 2012). By contrast, whilst the gain-of-function arising from the p.Met207Val mutation has been suggested to increase susceptibility to familial AF (Mechakra et al, 2019), this link remains to be demonstrated directly.…”

Section: Introductionmentioning

confidence: 95%

“…Whilst the precise mechanisms underlying AF are complex and poorly understood, AF-induced ionic remodeling and structural cardiac diseases are major factors in initiating and sustaining AF (Grandi et al, 2011; Colman et al, 2013; Koivumäki et al, 2014). However, genome-wide association studies suggested genetic variation contributes to AF susceptibility, with >100 AF-associated loci reported to date (Nielsen et al, 2018), including the atrial-selective transcription factor PITX2 (paired like homeodomain-2) that regulates membrane effector genes associated with AF (Gudbjartsson et al, 2007; Chinchilla et al, 2011; Kirchhof et al, 2011; Qiu et al, 2014; Tao et al, 2014; Lozano-Velasco et al, 2015; Pérez-Hernández et al, 2015; Bai et al, 2018; Mechakra et al, 2019). In these studies, Mechakra et al (2019) identified a non-synonymous mutation c.619A>G (p.Met207Val, rs138163892) of PITX2.…”

Section: Introductionmentioning

confidence: 99%

“…However, genome-wide association studies suggested genetic variation contributes to AF susceptibility, with >100 AF-associated loci reported to date (Nielsen et al, 2018), including the atrial-selective transcription factor PITX2 (paired like homeodomain-2) that regulates membrane effector genes associated with AF (Gudbjartsson et al, 2007; Chinchilla et al, 2011; Kirchhof et al, 2011; Qiu et al, 2014; Tao et al, 2014; Lozano-Velasco et al, 2015; Pérez-Hernández et al, 2015; Bai et al, 2018; Mechakra et al, 2019). In these studies, Mechakra et al (2019) identified a non-synonymous mutation c.619A>G (p.Met207Val, rs138163892) of PITX2. Functional analysis of the transactivation activity of wild-type and variant PITX2c revealed a gain-of-function of PITX2c (the PITX2 c isoform), leading to an increase in the mRNA level of KCNH2 (the α subunit of I Kr ), KCNQ1 (the α subunit of I Ks ), SCN1B (the β1 subunit of sodium channels that modulates I NaL ), GJA5 (Cx40), and GJA1 (Cx43) (Mechakra et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…In these studies, Mechakra et al (2019) identified a non-synonymous mutation c.619A>G (p.Met207Val, rs138163892) of PITX2. Functional analysis of the transactivation activity of wild-type and variant PITX2c revealed a gain-of-function of PITX2c (the PITX2 c isoform), leading to an increase in the mRNA level of KCNH2 (the α subunit of I Kr ), KCNQ1 (the α subunit of I Ks ), SCN1B (the β1 subunit of sodium channels that modulates I NaL ), GJA5 (Cx40), and GJA1 (Cx43) (Mechakra et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Bai

et al. 2019

Front. Physiol.

View full text Add to dashboard Cite

Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (INaL, IKs, and IKr) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

show abstract

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Bai

et al. 2019

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…It has previously been observed that PITX2 messenger RNA (mRNA) levels are reduced in the atrial cardiomyocytes (CMs) of sustained AF patients carrying risk variants at 4q25 (12). Additionally, PITX2 gain-of-function variants have also been associated with AF in humans, suggesting that expression levels of PITX2 targets must be tightly regulated for cardiac homeostasis (13,14). During vertebrate development, Pitx2 is a key regulator of left-right patterning of the body plan (15)(16)(17).…”

mentioning

confidence: 99%

Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model

Collins

Ahlberg

Hansen

et al. 2019

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

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c+/− fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c−/− larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.

show abstract

In Silico Characterization of Pathogenic Homeodomain Missense Mutations in the PITX2 Gene

Vetriselvan,

Manoharan,

Murugan

et al. 2024

Biochem Genet

View full text Add to dashboard Cite

A Novel PITX2c Gain-of-Function Mutation, p.Met207Val, in Patients With Familial Atrial Fibrillation

Cited by 17 publications

References 31 publications

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model

In Silico Characterization of Pathogenic Homeodomain Missense Mutations in the PITX2 Gene

Contact Info

Product

Resources

About