Novel α-Actinin 2 Variant Associated With Familial Hypertrophic Cardiomyopathy and Juvenile Atrial Arrhythmias

Girolami, Francesca; Iascone, Maria; Tomberli, Benedetta; Bardi, Sara; Benelli, Matteo; Marseglia, Giuseppina; Pescucci, Chiara; Pezzoli, Laura; Sana, Maria Elena; Basso, Cristina; Marziliano, Nicola; Merlini, Piera Angelica; Fornaro, Alessandra; Cecchi, Francesca; Torricelli, Francesca; Olivotto, Iacopo

doi:10.1161/circgenetics.113.000486

Cited by 73 publications

(58 citation statements)

References 42 publications

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“…5 Specific sarcomeric gene mutations have recently been described in atypical forms of HCM that relate to juvenile onset of AF in these patients. 17 Even polymorphisms in nonsarcomeric genes, encoding for proteins involved in the renin-angiotensin-aldosterone system and collagen synthesis, have shown to act as HCM disease modifiers, increasing the likelihood of AF development. 18 Therefore, it is not unexpected that AF often complicates the natural course of HCM, translating into a significant morbidity and mortality burden.…”

Section: Discussionmentioning

confidence: 99%

Left Atrial Size and Function in Hypertrophic Cardiomyopathy Patients and Risk of New-Onset Atrial Fibrillation

Debonnaire

Joyce

Hiemstra

et al. 2017

Circ: Arrhythmia and Electrophysiology

132

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Background— The value of left atrial (LA) diameter, volume, and strain to risk stratify hypertrophic cardiomyopathy patients for new-onset atrial fibrillation (AF) was explored. Methods and Results— A total of 242 hypertrophic cardiomyopathy patients without AF history were evaluated by (speckle-tracking) echocardiography. During mean follow-up of 4.8±3.7 years, 41 patients (17%) developed new-onset AF. Multivariable analysis showed LA volume (≥37 mL/m 2 ; hazard ratio, 2.68; 95% confidence interval, 1.30–5.54; P =0.008) and LA strain (≤23.4%; hazard ratio, 3.22; 95% confidence interval, 1.50–6.88; P =0.003), but not LA diameter (≥45 mm; hazard ratio, 1.67; 95% confidence interval, 0.84–3.32; P =0.145), as independent AF correlates. Importantly, 59% (n=24) of AF events occurred despite a baseline LA diameter <45 mm, observed in 185 patients. In this patient subset, LA strain (area under the curve 0.73) and LA volume (area under the curve 0.83) showed good predictive value for new-onset AF. Furthermore, patients with LA volume <37 versus ≥37 mL/m 2 and LA strain >23.4% versus ≤23.4% had superior 5-year AF-free survival of 93% versus 80% ( P =0.003) and 98% versus 74% ( P =0.002), respectively. Importantly, LA volume <37 mL/m 2 and strain >23.4% yielded high negative predictive value (93% and 98%, respectively) for new-onset AF. Likelihood ratio test indicated incremental value of LA volume assessment ( P =0.011) on top of LA diameter to predict new-onset AF in hypertrophic cardiomyopathy patients with LA diameter <45 mm, which tended to increase further by addition of LA strain ( P =0.126). Conclusions— LA diameter, volume, and strain all relate to new-onset AF in hypertrophic cardiomyopathy patients. In patients with normal LA size, however, both LA volume and strain further refine risk stratification for new-onset AF.

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Section: Discussionmentioning

confidence: 99%

Left Atrial Size and Function in Hypertrophic Cardiomyopathy Patients and Risk of New-Onset Atrial Fibrillation

Debonnaire

Joyce

Hiemstra

et al. 2017

Circ: Arrhythmia and Electrophysiology

132

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“…Our research identified another likely pathogenic mutation of ACTN2 which may be related to overlap phenotypes of cardiomyopathy and arrhythmias. This study provides a new case to perform further analyses on the relationship between ACTN2 mutations and overlap phenotypes, like the reported mutations p.A119T and M228T [Bagnall et al, 2014;Girolami et al, 2014]. In conclusion, we employed whole-exome sequencing in combination with a filtering strategy for cardiomyopathy-and arrhythmia-related genes to discover the genetic factors in a DCM family with brief syncope, ventricular tachycardia, and SCD.…”

Section: Discussionmentioning

confidence: 86%

“…However, most ACTN2 mutations were identified in HCM [Chiu et al, 2010;Haywood et al, 2016], and less mutations have been detected in DCM patients [Mohapatra et al, 2003;Zimmerman et al, 2010;Gonzalez-Garay et al, 2013]. What is more, only 2 reports found that variants of ACTN2 can lead to overlap phenotypes of cardiomyopathy and arrhythmias [Bagnall et al, 2014;Girolami et al, 2014]. Previous studies revealed that ACTN2 may play multiple functions in the Z-disc.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Fan

Huang

Jin

et al. 2019

Cytogenet Genome Res

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Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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“…Exome sequencing has been used to identify a mutation in the α-actinin-2 gene in a family associated with idiopathic ventricular fibrillation, left ventricular noncompaction and sudden death [23]. A targeted next-generation sequencing approach allowed the identification of a novel α-actinin-2 variant associated with midapical hypertrophic cardiomyopathy and juvenile-onset atrial fibrillation [24]. One study showed remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy [25].…”

Section: Discussionmentioning

confidence: 99%

Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Zhang

Zhang²,

Tang³

et al. 2016

Cardiology

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Objectives: Atrial ﬁbrosis, a marker of atrial structural remodeling, plays a critical role in atrial ﬁbrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β₁ (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF. Methods: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting. Results: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05). Conclusions: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

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Novel α-Actinin 2 Variant Associated With Familial Hypertrophic Cardiomyopathy and Juvenile Atrial Arrhythmias

Cited by 73 publications

References 42 publications

Left Atrial Size and Function in Hypertrophic Cardiomyopathy Patients and Risk of New-Onset Atrial Fibrillation

Left Atrial Size and Function in Hypertrophic Cardiomyopathy Patients and Risk of New-Onset Atrial Fibrillation

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

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