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1.
Int J Mol Sci ; 25(11)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38892395

ABSTRACT

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/ß-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia , Disease Models, Animal , Animals , Humans , Arrhythmogenic Right Ventricular Dysplasia/genetics , Arrhythmogenic Right Ventricular Dysplasia/metabolism , Arrhythmogenic Right Ventricular Dysplasia/pathology , Plakophilins/genetics , Plakophilins/metabolism , Desmoplakins/genetics , Desmoplakins/metabolism , Wnt Signaling Pathway/genetics , Desmoglein 2/genetics , Desmoglein 2/metabolism , Desmosomes/metabolism , Desmosomes/genetics , Mice
2.
Int J Mol Sci ; 22(20)2021 Oct 12.
Article in English | MEDLINE | ID: mdl-34681646

ABSTRACT

In the past two decades, genome editing has proven its value as a powerful tool for modeling or even treating numerous diseases. After the development of protein-guided systems such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), which for the first time made DNA editing an actual possibility, the advent of RNA-guided techniques has brought about an epochal change. Based on a bacterial anti-phage system, the CRISPR/Cas9 approach has provided a flexible and adaptable DNA-editing system that has been able to overcome several limitations associated with earlier methods, rapidly becoming the most common tool for both disease modeling and therapeutic studies. More recently, two novel CRISPR/Cas9-derived tools, namely base editing and prime editing, have further widened the range and accuracy of achievable genomic modifications. This review aims to provide an overview of the most recent developments in the genome-editing field and their applications in biomedical research, with a particular focus on models for the study and treatment of cardiac diseases.


Subject(s)
CRISPR-Cas Systems/genetics , Gene Editing/methods , Heart Diseases/genetics , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Heart Diseases/pathology , Humans , Models, Biological , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , RNA, Guide, Kinetoplastida/metabolism , Zinc Finger Nucleases/genetics , Zinc Finger Nucleases/metabolism
3.
Cells ; 10(10)2021 09 28.
Article in English | MEDLINE | ID: mdl-34685557

ABSTRACT

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p-value < 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Biomarkers/metabolism , Cardiomyopathies/genetics , MicroRNAs/metabolism , Adult , Case-Control Studies , Female , Humans , Male , Pilot Projects
4.
Genomics ; 113(2): 540-551, 2021 03.
Article in English | MEDLINE | ID: mdl-33482325

ABSTRACT

Cardiovascular diseases are among the leading causes of mortality worldwide. Besides environmental and genetic changes, these disorders can be influenced by processes which do not affect DNA sequence yet still play an important role in gene expression and which can be inherited. These so-called 'epigenetic' changes include DNA methylation, histone modifications, and ATP-dependent chromatin remodeling enzymes, which influence chromatin remodeling and gene expression. Next to these, microRNAs are non-coding RNA molecules that silence genes post-transcriptionally. Both epigenetic factors and microRNAs are known to influence cardiac development and homeostasis, in an individual fashion but also in a complex regulatory network. In this review, we will discuss how epigenetic factors and microRNAs interact with each other and how together they can influence cardiovascular diseases.


Subject(s)
Cardiovascular Diseases/genetics , Epigenesis, Genetic , MicroRNAs/metabolism , Animals , Humans , MicroRNAs/genetics
5.
Noncoding RNA Res ; 5(3): 144-152, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32954093

ABSTRACT

Obesity leads to an amplified risk of disease and contributes to the occurrence of type 2 diabetes, fatty liver disease, coronary heart disease, stroke, chronic kidney disease and various types of cancer. MicroRNAs (miRNAs), small non-coding RNA molecules of 20-25 nucleotides, can remain stable in plasma and have been studied as potential (predictive) biomarkers for obesity and related metabolic disorders. The aim of this study was to identify circulating miRNAs as biomarkers for obesity status and metabolic alterations in women. Circulating miR-216a and miR-155-5p were selected by miRNA expression profiling and validated by real time quantitative PCR in a validation cohort of 60 obese women and 60 normal weight-age-matched control women. This was supplemented by correlation analysis of the candidate miRNA and anthropometric variables, blood biochemistry and lipid profile markers. Circulating miR-216a was validated as a biomarker of obesity status with significantly reduced levels in obese women. Interestingly, this was associated with a negative correlation between the plasma miR-216a content and body mass index (BMI), waist circumference, mean arterial pressure (MAP), triglycerides, ratio of total cholesterol/high density lipoprotein (HDL)-cholesterol and high sensitivity-C reactive protein (hs-CRP).Taken together, we provide evidence for an abnormally expressed circulating miRNA, miR-216a, with additive value as a predictive marker for obesity that correlates with metabolic alterations presented by lipid profile and inflammatory markers.

6.
Int J Mol Sci ; 21(9)2020 May 11.
Article in English | MEDLINE | ID: mdl-32403456

ABSTRACT

In the last decade, the generation of cardiac disease models based on human-induced pluripotent stem cells (hiPSCs) has become of common use, providing new opportunities to overcome the lack of appropriate cardiac models. Although much progress has been made toward the generation of hiPSC-derived cardiomyocytes (hiPS-CMs), several lines of evidence indicate that two-dimensional (2D) cell culturing presents significant limitations, including hiPS-CMs immaturity and the absence of interaction between different cell types and the extracellular matrix. More recently, new advances in bioengineering and co-culture systems have allowed the generation of three-dimensional (3D) constructs based on hiPSC-derived cells. Within these systems, biochemical and physical stimuli influence the maturation of hiPS-CMs, which can show structural and functional properties more similar to those present in adult cardiomyocytes. In this review, we describe the latest advances in 2D- and 3D-hiPSC technology for cardiac disease mechanisms investigation, drug development, and therapeutic studies.


Subject(s)
Cardiovascular Diseases/therapy , Cell Culture Techniques/methods , Cell Differentiation , Induced Pluripotent Stem Cells/physiology , Models, Cardiovascular , Myocytes, Cardiac/physiology , Cardiovascular Diseases/diagnosis , Cells, Cultured , Humans , Induced Pluripotent Stem Cells/cytology , Myocytes, Cardiac/cytology , Tissue Engineering/methods , Tissue Scaffolds
8.
J Clin Med ; 8(12)2019 Dec 12.
Article in English | MEDLINE | ID: mdl-31842377

ABSTRACT

The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.

9.
Cells ; 8(7)2019 07 18.
Article in English | MEDLINE | ID: mdl-31323768

ABSTRACT

Since their discovery 20 years ago, microRNAs have been related to posttranscriptional regulation of gene expression in major cardiac physiological and pathological processes. We know now that cardiac muscle phenotypes are tightly regulated by multiple noncoding RNA species to maintain cardiac homeostasis. Upon stress or various pathological conditions, this class of non-coding RNAs has been found to modulate different cardiac pathological conditions, such as contractility, arrhythmia, myocardial infarction, hypertrophy, and inherited cardiomyopathies. This review summarizes and updates microRNAs playing a role in the different processes underlying the pathogenic phenotypes of cardiac muscle and highlights their potential role as disease biomarkers and therapeutic targets.


Subject(s)
Circulating MicroRNA/genetics , Heart Diseases/genetics , Animals , Biomarkers/blood , Circulating MicroRNA/blood , Circulating MicroRNA/metabolism , Heart Diseases/blood , Heart Diseases/metabolism , Heart Diseases/therapy , Humans , RNAi Therapeutics/methods
10.
Heart Rhythm ; 16(5): 773-780, 2019 05.
Article in English | MEDLINE | ID: mdl-30453078

ABSTRACT

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive. OBJECTIVE: The purpose of this study was to identify the underlying genetic cause in probands with ACM. METHODS: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes-DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. RESULTS: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. CONCLUSION: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Adult , Apoptosis Regulatory Proteins/genetics , Codon, Nonsense , Desmosomes/genetics , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Repressor Proteins/genetics
11.
Cardiovasc Res ; 115(4): 739-751, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30304392

ABSTRACT

AIMS: Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. METHODS AND RESULTS: We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/ß-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. CONCLUSION: Down-regulation of the canonical Wnt/ß-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/ß-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Codon, Nonsense , Desmoglein 2/genetics , MicroRNAs/genetics , Myocardium/metabolism , Wnt Signaling Pathway/genetics , Animals , Arrhythmogenic Right Ventricular Dysplasia/metabolism , Arrhythmogenic Right Ventricular Dysplasia/pathology , Disease Models, Animal , Fibrosis , Gene Expression Regulation , Gene Regulatory Networks , Genetic Predisposition to Disease , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/metabolism , Myocardium/ultrastructure , Phenotype , Transcriptome
12.
Mol Ther ; 27(3): 584-599, 2019 03 06.
Article in English | MEDLINE | ID: mdl-30559069

ABSTRACT

Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.


Subject(s)
Cardiomyopathies/metabolism , Heart Failure/metabolism , Heart Transplantation/methods , MicroRNAs/metabolism , Myocardium/metabolism , Animals , Cardiomyopathies/genetics , Cell Proliferation/physiology , Heart Failure/genetics , Humans , Mice , MicroRNAs/genetics , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/physiology , Ventricular Remodeling/genetics , Ventricular Remodeling/physiology
13.
Circ Genom Precis Med ; 11(10): e002123, 2018 10.
Article in English | MEDLINE | ID: mdl-30354300

ABSTRACT

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, and most of them are found in genes encoding mechanical junction proteins of the intercalated disk. METHODS: Whole-exome sequencing was performed on the proband of an ACM family. Sanger sequencing was used to screen for mutations the tight junction protein 1 ( TJP1) gene in unrelated patients. Predictions of local structure content and molecular dynamics simulations were performed to investigate the structural impact of the variants. RESULTS: A novel c.2006A>G p.(Y669C) variant in TJP1 gene was identified by whole-exome sequencing in a patient with ACM. TJP1 encodes zonula occludens 1, an intercalated disk protein interacting with proteins of gap junctions and area composita. Additional rare TJP1 variants have been identified in 1 of 40 Italian probands (c.793C>T p.(R265W)) with arrhythmogenic right ventricular cardiomyopathy and in 2 of 43 Dutch/German patients (c. 986C>T, p.(S329L) and c.1079A>T, p.(D360V)) with dilated cardiomyopathy and recurrent ventricular tachycardia. The p.(D360V) variant was identified in a proband also carrying the p.(I156N) pathogenic variant in DSP. All 4 TJP1 variants are predicted to be deleterious and affect highly conserved amino acids, either at the GUK (guanylate kinase)-like domain (p.(Y669C)) or at the disordered region of the protein between the PDZ2 and PDZ3 domains (p.(R265W), p.(S329L), and p.(D360V)). The local unfolding induced by the former promotes structural rearrangements of the GUK domain, whereas the others are predicted to impair the function of the disordered region. Furthermore, rare variants in TJP1 are statistically enriched in patients with ACM relative to controls. CONCLUSIONS: We provide here the first evidence linking likely pathogenic TJP1 variants to ACM. Prevalence and pathogenic mechanism of TJP1-mediated ACM remain to be determined.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Zonula Occludens-1 Protein/genetics , Adult , Arrhythmogenic Right Ventricular Dysplasia/epidemiology , Arrhythmogenic Right Ventricular Dysplasia/metabolism , Arrhythmogenic Right Ventricular Dysplasia/pathology , Female , Germany/epidemiology , Humans , Male , Myocardium/metabolism , Myocardium/pathology , Netherlands/epidemiology , Prevalence , Exome Sequencing , Zonula Occludens-1 Protein/metabolism
14.
Article in English | MEDLINE | ID: mdl-29038103

ABSTRACT

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 (PKP2) gene, 2 a deletion of only PKP2 exon 4, 1 a deletion of the PKP2 exons 6 to 11, 1 a PKP2 duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 (DSC2) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both DSC2 and desmoglein-2 genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. CONCLUSIONS: Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Desmosomes/genetics , Gene Rearrangement , Action Potentials , Adolescent , Adult , Aged , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/physiopathology , DNA Copy Number Variations , DNA Mutational Analysis , Desmocollins/genetics , Desmoglein 2/genetics , Desmoplakins/genetics , Electrocardiography , Electrophysiologic Techniques, Cardiac , Female , Gene Deletion , Gene Dosage , Gene Duplication , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Heart Rate , Heredity , Humans , Italy , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Pedigree , Phenotype , Plakophilins/genetics , Point Mutation , Risk Factors , Young Adult , gamma Catenin
15.
Oncotarget ; 8(36): 60640-60655, 2017 Sep 01.
Article in English | MEDLINE | ID: mdl-28948000

ABSTRACT

Wnt/ß-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/ß-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue. In this review, we summarize the conflicting published data regarding the Wnt/ß-catenin signaling contribution to AC pathogenesis and we report the identification of a new potential therapeutic molecule that prevents myocyte injury and cardiac dysfunction due to desmosome mutations in vitro and in vivo by interfering in this signaling pathway. Finally, we underline the potential function of microRNAs, epigenetic regulatory RNA factors reported to participate in several pathological responses in heart tissue and in the Wnt signaling network, as important modulators of Wnt/ß-catenin signaling transduction in AC. Elucidation of the precise regulatory mechanism of Wnt/ß-catenin signaling in AC molecular pathogenesis could provide fundamental insights for new mechanism-based therapeutic strategy to delay the onset or progression of this cardiac disease.

16.
Eur J Hum Genet ; 25(10): 1165-1169, 2017 10.
Article in English | MEDLINE | ID: mdl-28699631

ABSTRACT

Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM. In Family B, one patient was identified to carry mutations in α-T-catenin (CTTNA3) and ß-myosin (MYH7) genes, but he does not fulfill the current diagnostic criteria neither for ACM nor for HCM. Interestingly, the double heterozygotes showed a variable clinical expression of both cardiomyopathies and they do not exhibit a more severe phenotype than family members carrying only one of the two mutations.


Subject(s)
Arrhythmias, Cardiac/genetics , Cardiac Myosins/genetics , Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , Desmoplakins/genetics , Myosin Heavy Chains/genetics , Phenotype , alpha Catenin/genetics , Adolescent , Adult , Aged , Arrhythmias, Cardiac/diagnosis , Cardiomyopathy, Hypertrophic/diagnosis , Female , Heterozygote , Humans , Male , Middle Aged , Mutation , Pedigree , alpha Catenin/metabolism
18.
J Cardiovasc Med (Hagerstown) ; 17(6): 399-407, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26990921

ABSTRACT

Sudden death, ventricular arrhythmia and heart failure are common features in arrhythmogenic right-ventricular cardiomyopathy (ARVC), an inheritable heart muscle disease, characterized by clinical and genetic heterogeneity. So far, 13 disease genes have been identified, responsible for around 60% of all ARVC cases. In this review, we summarize the main clinical and pathological aspects of ARVC, focusing on the importance of the genetic testing and the application of the new sequencing techniques referred to next generation sequencing technology.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , High-Throughput Nucleotide Sequencing/methods , Mutation , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/therapy , Death, Sudden, Cardiac/etiology , Genetic Predisposition to Disease , Genetic Testing/methods , Humans
19.
J Mol Cell Cardiol ; 89(Pt A): 27-34, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26546166

ABSTRACT

After the recent description of the human genome by the ENCODE and the FANTOM consortia, major attention has been addressed to the so-called "genomic noise", which mainly consists of noncoding RNAs (ncRNAs). Among them, microRNAs and long non-coding RNAs have been demonstrated to modulate gene expression and to be involved in several human diseases. Since ncRNAs and their targets are encoded in the genome, genetic principles apply. Common variants are supposed to influence the expression level and the functionality of ncRNAs, with subsequent differential regulation of their target genes. Moreover, several reports showed that polymorphisms in ncRNA or their target genes play a role in the development of cardiovascular adverse phenotype. Here, we provide an overview of the effects of these variations in cardiovascular diseases.


Subject(s)
Cardiovascular Diseases/genetics , Epigenesis, Genetic , Genetic Variation , RNA, Untranslated/genetics , Animals , Humans , Polymorphism, Single Nucleotide/genetics , RNA, Untranslated/metabolism
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