Cardiomyopathy
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FLNC Missense Variants in Familial Noncompaction Cardiomyopathy
Cardiogenetics 2019; volume 9:8181 FLNC missense variants than 2 according to current echocardio- in familial noncompaction graphic criteria, or 2.3 on CMR.1,2 Correspondence: Jaap I. van Waning, Approximately 10% of patients diagnosed Department of Clinical Genetics, EE 2038, cardiomyopathy with NCCM have concurrent congenital Erasmus MC, POB 2040, 3000CA Rotterdam, heart defects (CHD).3,4 the Netherlands. Tel.: +3107038388 - Fax: +3107043072. Jaap I. van Waning,1 In 30-40% of cases diagnosed with E-mail: [email protected] Yvonne M. Hoedemaekers,2 NCCM a pathogenic variant can be identi- 2,3 4 Wouter P. te Rijdt, Arne I. Jpma, fied. Around 80% of these pathogenic vari- Acknowledgements: JVW was supported by a Daphne Heijsman,4 Kadir Caliskan,5 ants involve the same sarcomere genes, that grant from the Jaap Schouten Foundation. Elke S. Hoendermis,6 are the major causes for hypertrophic car- WPTR was supported by a Young Talent Program (CVON PREDICT) grant 2017T001 Tineke P. Willems,7 diomyopathy (HCM) and dilated cardiomy- - Dutch Heart Foundation. 8 opathy (DCM), in particular MYH7, Arthur van den Wijngaard, 5,6 3 MYBPC3 and TTN. Filamin C (FLNC) Albert Suurmeijer, Conflict of interest: the authors declare no plays a central role in muscle functioning Marjon A. van Slegtenhorst,1 potential conflict of interest. by maintaining the structural integrity of the Jan D.H. Jongbloed,2 muscle fibers. Pathogenic variants in FLNC Received for publication: 20 March 2019. Danielle F. Majoor-Krakauer,1 2 were found to be associated with a wide Revision received: 29 July 2019. Paul A. -
Post-Mortem Whole-Exome Analysis in a Large Sudden Infant Death Syndrome Cohort with a Focus on Cardiovascular and Metabolic Genetic Diseases
European Journal of Human Genetics (2017) 25, 404–409 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/17 www.nature.com/ejhg ARTICLE Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases Jacqueline Neubauer*,1, Maria Rita Lecca2, Giancarlo Russo2, Christine Bartsch3, Argelia Medeiros-Domingo4, Wolfgang Berger5,6,7 and Cordula Haas1 Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. -
The Cytoskeleton in Cell-Autonomous Immunity: Structural Determinants of Host Defence
Mostowy & Shenoy, Nat Rev Immunol, doi:10.1038/nri3877 The cytoskeleton in cell-autonomous immunity: structural determinants of host defence Serge Mostowy and Avinash R. Shenoy Medical Research Council Centre of Molecular Bacteriology and Infection (CMBI), Imperial College London, Armstrong Road, London SW7 2AZ, UK. e‑mails: [email protected] ; [email protected] doi:10.1038/nri3877 Published online 21 August 2015 Abstract Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence. 1 Mostowy & Shenoy, Nat Rev Immunol, doi:10.1038/nri3877 Cell-autonomous immunity, which is defined as the ability of a host cell to eliminate an invasive infectious agent, is a first line of defence against microbial pathogens 1 . It relies on antimicrobial proteins, specialized degradative compartments and programmed host cell death 1–3 . Cell- autonomous immunity is mediated by tiered innate immune signalling networks that sense microbial pathogens and stimulate downstream pathogen elimination programmes. Recent studies on host– microorganism interactions show that components of the host cell cytoskeleton are integral to the detection of bacterial pathogens as well as to the mobilization of antibacterial responses (FIG. -
Genetic Variation Screening of TNNT2 Gene in a Cohort of Patients with Hypertrophic and Dilated Cardiomyopathy
Physiol. Res. 61: 169-175, 2012 https://doi.org/10.33549/physiolres.932157 Genetic Variation Screening of TNNT2 Gene in a Cohort of Patients With Hypertrophic and Dilated Cardiomyopathy M. JÁCHYMOVÁ1, A. MURAVSKÁ1, T. PALEČEK2, P. KUCHYNKA2, H. ŘEHÁKOVÁ1, S. MAGAGE2, A. KRÁL2, T. ZIMA1, K. HORKÝ2, A. LINHART2 1Institute of Clinical Chemistry and Laboratory Diagnostics, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic, 2Second Department of Internal Medicine – Clinical Department of Cardiology and Angiology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic Received February 1, 2011 Accepted October 17, 2011 On-line January 31, 2012 Summary Introduction Mutations in troponin T (TNNT2) gene represent the important part of currently identified disease-causing mutations in Cardiomyopathies are generally defined as hypertrophic (HCM) and dilated (DCM) cardiomyopathy. The aim myocardial disorders in which the heart muscle is of this study was to analyze TNNT2 gene exons in patients with structurally and functionally abnormal, in the absence of HCM and DCM diagnosis to improve diagnostic and genetic coronary artery disease, hypertension, valvular disease consultancy in affected families. All 15 exons and their flanking and congenital heart disease sufficient to cause the regions of the TNNT2 gene were analyzed by DNA sequence observed myocardial abnormality (Elliott et al. 2008). analysis in 174 patients with HCM and DCM diagnosis. We According to the morphological and functional phenotype identified genetic variations in TNNT2 exon regions in 56 patients the diagnosis of hypertrophic and dilated cardiomyopathy and genetic variations in TNNT2 intron regions in 164 patients. -
Genetic Mutations and Mechanisms in Dilated Cardiomyopathy
Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, … , Jessica R. Golbus, Megan J. Puckelwartz J Clin Invest. 2013;123(1):19-26. https://doi.org/10.1172/JCI62862. Review Series Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Find the latest version: https://jci.me/62862/pdf Review series Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, Jessica R. Golbus, and Megan J. Puckelwartz Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of conges- tive heart failure. -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
Minding the Calcium Store: Ryanodine Receptor Activation As a Convergent Mechanism of PCB Toxicity
Pharmacology & Therapeutics 125 (2010) 260–285 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate Editor: Carey Pope Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity Isaac N. Pessah ⁎, Gennady Cherednichenko, Pamela J. Lein Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA article info abstract Keywords: Chronic low-level polychlorinated biphenyl (PCB) exposures remain a significant public health concern since Ryanodine receptor (RyR) results from epidemiological studies indicate that PCB burden is associated with immune system Calcium-induced calcium release dysfunction, cardiovascular disease, and impairment of the developing nervous system. Of these various Calcium regulation adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in Polychlorinated biphenyls PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter Triclosan fi 2+ Bastadins the spatial and temporal delity of Ca signals through one or more receptor-mediated processes. This Polybrominated diphenylethers review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in Developmental neurotoxicity muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The Activity dependent plasticity molecular and cellular mechanisms by which non-coplanar PCBs and related structures alter local and global Ca2+ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed. © 2009 Elsevier Inc. All rights reserved. Contents 1. Introduction ............................................... 260 2. Ryanodine receptor macromolecular complexes: significance to polychlorinated biphenyl-mediated Ca2+ dysregulation . -
Next Generation Sequencing for Molecular Confirmation of Hereditary
Arch Cardiol Mex. 2015;85(1):68---72 www.elsevier.com.mx SPECIAL ARTICLE Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes a,∗ b b b Manlio F. Márquez , David Cruz-Robles , Selene Ines-Real , Gilberto Vargas-Alarcón , a Manuel Cárdenas a Departamento de Electrofisiología, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico b Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico Received 26 March 2014; accepted 8 December 2014 KEYWORDS Abstract Hereditary sudden cardiac death syndromes comprise a wide range of diseases result- Arrhythmias; ing from alteration in cardiac ion channels. Genes involved in these syndromes represent diverse Hereditary sudden mutations that cause the altered encoding of the diverse proteins constituting these channels, cardiac death thus affecting directly the currents of the corresponding ions. In the present article we will syndromes; briefly review how to arrive to a clinical diagnosis and we will present the results of molecular Right ventricle genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National arrhythmogenic Institute of Cardiology of Mexico City. cardiomyopathy; © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México Brugada syndrome S.A. All rights reserved. PALABRAS CLAVE Confirmación diagnóstica molecular mediante secuenciación masiva de nueva Arritmias; generación (‘‘next generation sequencing’’) en síndromes hereditarios de muerte Síndromes súbita cardíaca hereditarios de Resumen Los síndromes hereditarios de muerte súbita cardíaca comprenden una amplia gama muerte súbita; Displasia de enfermedades resultantes de la alteración en los canales iónicos cardíacos. Los genes implicados en estos síndromes presentan mutaciones que causan alteraciones de las diversas Arritmogénica del proteínas que constituyen estos canales y que, por lo tanto, afectan directamente a las difer- ventriculo derecho; entes corrientes iónicas. -
Sarcomere Gene Variants Act As a Genetic Trigger Underlying the Development of Left Ventricular Noncompaction
www.nature.com/pr BASIC SCIENCE ARTICLE Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction Asami Takasaki1, Keiichi Hirono1, Yukiko Hata2, Ce Wang1,3, Masafumi Takeda4, Jun K Yamashita4, Bo Chang1, Hideyuki Nakaoka1, Mako Okabe1, Nariaki Miyao1, Kazuyoshi Saito1, Keijiro Ibuki1, Sayaka Ozawa1, Michikazu Sekine5, Naoki Yoshimura6, Naoki Nishida2, Neil E. Bowles7 and Fukiko Ichida1 BACKGROUND: Left ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC. METHODS AND RESULTS: We screened 82 Japanese patients (0–35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p. Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway. CONCLUSIONS: Sarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease. -
Non-Coding Rnas in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases
Review Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases Estefania Lozano-Velasco 1,2 , Amelia Aranega 1,2 and Diego Franco 1,2,* 1 Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; [email protected] (E.L.-V.); [email protected] (A.A.) 2 Fundación Medina, 18016 Granada, Spain * Correspondence: [email protected] Abstract: Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, our current understanding of the functional roles of non-coding RNAs have progressively increased. microRNAs represent the most studied type of small ncRNAs and it has been demonstrated that miRNAs play essential roles in multiple biological contexts, including normal development and diseases. In this review, we provide a comprehensive analysis of the functional contribution of non-coding RNAs, primarily microRNAs, to the normal configuration of the cardiac action potential, as well as their association to distinct types of arrhythmogenic cardiac diseases. Keywords: cardiac arrhythmia; microRNAs; lncRNAs; cardiac action potential Citation: Lozano-Velasco, E.; Aranega, A.; Franco, D. Non-Coding RNAs in the Cardiac Action Potential 1. The Electrical Components of the Adult Heart and Their Impact on Arrhythmogenic The adult heart is a four-chambered organ that propels oxygenated blood to the entire Cardiac Diseases. Hearts 2021, 2, body. It is composed of atrial and ventricular chambers, each of them with distinct left and 307–330. -
Novel Pathogenic Variants in Filamin C Identified in Pediatric Restrictive Cardiomyopathy
Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy Jeffrey Schubert1, 2, Muhammad Tariq3, Gabrielle Geddes4, Steven Kindel4, Erin M. Miller5, and Stephanie M. Ware2. 1 Department of Molecular Genetics, Microbiology, and Biochemistry, University of Cincinnati College of Medicine, Cincinnati, OH; 2 Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN; 3 Faculty of Applied Medical Science, University of Tabuk, Tabuk, Kingdom of Saudi Arabia; 4Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; 5Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Correspondence: Stephanie M. Ware, MD, PhD Department of Pediatrics Indiana University School of Medicine 1044 W. Walnut Street Indianapolis, IN 46202 Telephone: 317 274-8939 Email: [email protected] Grant Sponsor: The project was supported by the Children’s Cardiomyopathy Foundation (S.M.W.), an American Heart Association Established Investigator Award 13EIA13460001 (S.M.W.) and an AHA Postdoctoral Fellowship Award 12POST10370002 (M.T.). ___________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Schubert, J., Tariq, M., Geddes, G., Kindel, S., Miller, E. M., & Ware, S. M. (2018). Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy. Human Mutation, 0(ja). https://doi.org/10.1002/humu.23661 Abstract Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained especially in early childhood. -
Development of the Stria Vascularis and Potassium Regulation in the Human Fetal Cochlea: Insights Into Hereditary Sensorineural Hearing Loss
Development of the Stria Vascularis and Potassium Regulation in the Human Fetal Cochlea: Insights into Hereditary Sensorineural Hearing Loss Heiko Locher,1,2 John C.M.J. de Groot,2 Liesbeth van Iperen,1 Margriet A. Huisman,2 Johan H.M. Frijns,2 Susana M. Chuva de Sousa Lopes1,3 1 Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 2 Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 3 Department for Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium Received 25 August 2014; revised 2 February 2015; accepted 2 February 2015 ABSTRACT: Sensorineural hearing loss (SNHL) is dynamics of key potassium-regulating proteins. At W12, one of the most common congenital disorders in humans, MITF1/SOX101/KIT1 neural-crest-derived melano- afflicting one in every thousand newborns. The majority cytes migrated into the cochlea and penetrated the base- is of heritable origin and can be divided in syndromic ment membrane of the lateral wall epithelium, and nonsyndromic forms. Knowledge of the expression developing into the intermediate cells of the stria vascula- profile of affected genes in the human fetal cochlea is lim- ris. These melanocytes tightly integrated with Na1/K1- ited, and as many of the gene mutations causing SNHL ATPase-positive marginal cells, which started to express likely affect the stria vascularis or cochlear potassium KCNQ1 in their apical membrane at W16. At W18, homeostasis (both essential to hearing), a better insight KCNJ10 and gap junction proteins GJB2/CX26 and into the embryological development of this organ is GJB6/CX30 were expressed in the cells in the outer sul- needed to understand SNHL etiologies.