A novel splicing variant in FLNC gene responsible for a highly penetrant familial dilated cardiomyopathy in an extended Iranian family

Nozari, Ahoura; Aghaei-Moghadam, Ehsan; Zeinaloo, Ali Akbar; Mollazadeh, Reza; Majnoon, Mohammad-Taghi; Alavi, Afagh; Firouzabadi, Saghar Ghasemi; Mohammadzadeh, Akbar; Banihashemi, Susan; Nikzaban, Mehrnoush; Najmabadi, Hossein; Behjati, Farkhondeh

doi:10.1016/j.gene.2018.03.044

Cited by 13 publications

(13 citation statements)

References 17 publications

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“…Truncating mutations in Filamin C (FLNC) were investigated in three studies which reported frequent premature sudden death and ventricular arrhythmias (82%) in the study participants. 13,14 Additionally, Ser96Ala polymorphisms in Histidine-Rich Calcium binding protein were investigated by one study and were strongly associated with life-threatening ventricular arrhythmias [HR 9.62; 95% CI (2.18-42.39)]. S2…”

Section: Geneticsmentioning

confidence: 99%

Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review

et al. 2020

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Aims Patients with non-ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter-defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow-up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74-1.00)], hypertension [HR 1.95; 95% CI (1.26-3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32-13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19-1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02-7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non-sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin-C (FLNC)] were associated with arrhythmic outcome in non-pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non-)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter-defibrillator implantation.

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Section: Geneticsmentioning

confidence: 99%

Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review

et al. 2020

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“…Affected individuals develop heart failure that requires heart transplantation in some cases of children and adults [116]. A splicing mutation in FLNC: c.2389+1G>A could be responsible for cardiac-restricted dilated cardiomyopathy (DCM) [104]. In addition, FLNC variants have been associated with multiple types of CM such as restrictive cardiomyopathy (RCM) and arrhythmic cardiomyopathy (ACM) in the absence of skeletal muscle pathology [16,88,89,112,113,116,119,121,136].…”

Section: Flnc Mutation Development In Cardiomyopathymentioning

confidence: 99%

Structure and Function of Filamin C in the Muscle Z-Disc

Mao

Nakamura

2020

IJMS

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Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

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“…FLNC encodes filamin-c, which is a huge cytolinker protein involved in linkage of the area composita, costameres, and actin filaments. The relevance of FLNC mutations for development of different cardiomyopathies, such as HCM ( Valdes-Mas et al, 2014 ), RCM ( Brodehl et al, 2016b ), and DCM ( Begay et al, 2016 ; Nozari et al, 2018 ) has been more recently recognized. In addition, mutations in FLNC cause ACM ( Begay et al, 2018 ; Hall et al, 2019 , 2020 ; Augusto et al, 2020 ; Brun et al, 2020 ).…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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A novel splicing variant in FLNC gene responsible for a highly penetrant familial dilated cardiomyopathy in an extended Iranian family

Cited by 13 publications

References 17 publications

Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review

Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review

Structure and Function of Filamin C in the Muscle Z-Disc

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

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