Posts Tagged: genetics

Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function

Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function

Tamer Sallam, Jaspreet Sandhu, Peter Tontonoz

Pipeline of long noncoding RNA (lncRNA) discovery and characterization. ASO indicates antisense oligonucleotide; ChiRP, chromatin isolation by RNA purification; qPCR, quantitative polymerase chain reaction; RAP, RNA antisense purification; and RIP, RNA immunoprecipitation. [Powerpoint File]

Heart Failure in Pediatric Patients With Congenital Heart Disease

Heart Failure in Pediatric Patients With Congenital Heart Disease

Robert B. Hinton, Stephanie M. Ware

Genes causing congenital heart disease (CHD) and cardiomyopathy form a complex network. The network diagrams were generated using ToppCluster (www.toppcluster.cchmc.org) software. Gene lists were derived from clinically available next-generation sequencing panels for cardiomyopathy genes (n=50) and CHD genes (n=44). A, Abstracted cluster network showing a selected subset of features from the following categories: Gene ontology (GO): molecular function; GO: biological processes; GO: cellular component; human phenotype; mouse phenotype; pathway; disease (cardiomyopathy and CHD). The features are color coded by category and connected to cardiomyopathy (white circle) and CHD gene nodes. B, Gene level network with nodes (blue) selected from features in GO: biological processes category. The network illustrates that regulation of cellular component of movement, actin filament-based processes, and cardiac chamber morphogenesis are shared in common between cardiomyopathy and CHD genes, whereas regulation of force of heart contraction and tube development are unshared. [Powerpoint File]

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

NOTCH signaling in congenital heart disease (CHD) (A) the outline of NOTCH signaling pathway showing signal-sending cell in yellow and signal receiving cell in green. B, Syndromes and CHD associated with NOTCH pathway gene mutations. BAV indicates bicuspid aortic valve; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy-associated defects; NA, not applicable; NICD, Notch intracellular domain; VSD, ventricular septal defect; TA, truncus arteriosus; and TOF, tetralogy of Fallot. [Powerpoint File]

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

A, Outline of human heart development. The x axis displays days of human and mouse gestation. B, The spectrum of congenital heart disease from mild to severe. The lesions indicated as “severe” are expected to require intervention in the first year of life. Classes of CHD based on proposed developmental-genetic mechanisms are indicated in parentheses. C, Genetic causes of CHD identified to date. ASD indicates atrial septal defect; CHD, congenital heart disease; CoA, coarctation of the aorta; CTD, conotruncal defect; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy; LVO, left ventricular outflow obstruction; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; and VSD, ventricular septal defect. [Powerpoint File]

Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Kiran Musunuru, Sekar Kathiresan

The cumulative effects of genetic variants that raise plasma low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels on the risk of myocardial infarction (MI). SD indicates standard deviation. [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Schematic representation of a cardiomyocyte displaying the proteins involved in the pathogenesis of the primary electric disorders. A, potassium (IKr; B), calcium (ICaL), and (C) sodium (INa) channel structures and subunits are shown. CASQ2 indicates calsequentrin-2; PLN, cardiac phospholamban; RyR2, ryanodine receptor 2; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; and SR, sarcoplasmic reticulum (Illustration credit: Ben Smith). [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Schematic representation of a cardiomyocyte exhibiting proteins involved in the pathogenesis of the inherited cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal proteins, and nuclear envelope proteins. MLP indicates cysteine and glycine-rich protein 3 (also known as muscle LIM [Lin-11, Islet-1, Mec-3] protein) (Illustration credit: Ben Smith). [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Structure and mutational clusters of RyR2. A, Clusters with frequent mutations are depicted with their location along the protein. Clusters are represented by numbered red lines. Individual mutations outside the canonical clusters are depicted as yellow dots. B, Clusters are represented by boxes, with the amino acid (AA) range of the clusters and the percentage of published mutations for each cluster (AA numbering refers to the human RyR2 protein sequence). The numbers in A correspond to the clusters shown in B. SR indicates sarcoplasmic reticulum (Illustration credit: Ben Smith). [Powerpoint File]

The Genetics of Pulmonary Arterial Hypertension

The Genetics of Pulmonary Arterial Hypertension

Eric D. Austin, James E. Loyd

Simplified schematic of the proteins encoded by the genes with mutations known to associate with pulmonary arterial hypertension (PAH), with a focus on the BMP signaling pathway but addition of recently described mutations. Genes with mutations known to associate with PAH include BMPR2, ALK1, Endoglin, Smad9 (encodes SMAD 8), CAV1, KCNK3, and EIF2AK4. Possible resultant signaling or effects of protein actions are briefly listed. Of note, Smad-independent effects of BMP signaling abnormalities are not shown but may contribute to PAH pathogenesis, such as alterations in cytoskeletal dynamics, cell survival, and mitochondrial metabolism. BMPR2 indicates bone morphogenic protein receptor type 2; and TGF-β, transforming growth factor-β. [Powerpoint File]

Emerging Directions in the Genetics of Atrial Fibrillation

Emerging Directions in the Genetics of Atrial Fibrillation

Nathan R. Tucker, Patrick T. Ellinor

Known genetic pathways for atrial fibrillation (AF) pathogenesis. Schematic of known AF-related genes derived from previous studies. Genes listed include those where coding variation was identified in familial AF and candidate gene screens, as well as the genes suggested to be implicated in AF based on genome-wide association studies (GWAS). Names listed in red indicate those identified by familial studies and candidate gene screens, whereas those listed in gray are gene targets implicated by GWAS. [Powerpoint File]

Heart Failure Compendium: Genetic Cardiomyopathies Causing Heart Failure

Heart Failure Compendium: Genetic Cardiomyopathies Causing Heart Failure

Thomas J. Cahill, Houman Ashrafian, Hugh Watkins

Cardiac magnetic resonance imaging (MRI) scan demonstrating features of phenotypic overlap across the standard cardiomyopathy classification. Horizontal long-axis (A), vertical long-axis (B), short-axis (C), and late gadolinium-enhanced (D) cardiac MRIs from a patient presenting with symptoms of heart failure. This study demonstrates a mildly dilated left ventricle with severely impaired systolic function (ejection fraction, 35%). Significant left ventricular hypertrophy is seen and is most pronounced in the septum. There was late gadolinium enhancement in the basal midseptum, also involving the inferior right ventricular–left ventricular junction (D). Additionally, the lateral wall shows prominent trabeculation, but this does not reach the current diagnostic threshold for left ventricular noncompaction. The features manifest in this scan are most consistent with hypertrophic cardiomyopathy (HCM) in a burnt-out phase, but HCM and left ventricular noncompaction cardiomyopathy are subject to phenotypic and pathogenic overlap. [Powerpoint File]

Overview of High Throughput Sequencing Technologies to Elucidate Molecular Pathways in Cardiovascular Diseases

Overview of High Throughput Sequencing Technologies to Elucidate Molecular Pathways in Cardiovascular Diseases

Jared M. Churko, Gary L. Mantalas, Michael P. Snyder, Joseph C. Wu

Nanopore technology. Third-generation sequencing is expected to measure the change in ion flow (current) within a membrane as small molecules are passed through a small pore inside the membrane. Different current profiles will, therefore, indicate which nucleotide passed through and in which order. [Powerpoint File]

Inherited Dysfunction of Sarcoplasmic Reticulum Ca2+ Handling and Arrhythmogenesis

Inherited Dysfunction of Sarcoplasmic Reticulum Ca2+ Handling and Arrhythmogenesis

Silvia G. Priori, S.R. Wayne Chen

CICR, SOICR, and triggered arrhythmia. Left (in blue) depicts the mechanism of CICR, in which an action potential activates the voltage-dependent L-type Ca2+ channel, leading to a small Ca2+ influx. This Ca2+ entry opens the RyR2 channel in the SR, resulting in SR Ca2+ release and muscle contraction. Right (in red) denotes the mechanism of SOICR, in which spontaneous SR Ca2+ release or Ca2+ spillover occurs under conditions of SR Ca2+ overload caused, for example, by stress via the β-adrenergic receptor (b-AR)/PKA/phospholamban (PLB) signaling pathway. SOICR can activate the NCX, which, in turn, can lead to DADs and triggered activities. (Illustration Credit: Cosmocyte/Ben Smith). [Powerpoint File]

Cardiovascular Pharmacogenomics

Cardiovascular Pharmacogenomics

Dan M. Roden, Julie A. Johnson, Stephen E. Kimmel, Ronald M. Krauss, Marisa Wong Medina, Alan Shuldiner, Russell A. Wilke

Therapeutic index. For any drug, there is a relationship between dose and efficacy (black lines) and a second relationship between dose and toxicity (gray lines). These curves are derived from populations and efficacy may be incomplete, as indicated in these examples. The arrows on each plot identify the dose at which 50% of the response is seen, and the therapeutic index is indicated by the open arrow at the bottom of each plot. Some drugs considered here, such as warfarin and clopidogrel, have narrow therapeutic indices, whereas others (β-blockers, statins) have wider ones. DNA variants may modulate the relationship between efficacy and toxicity in populations and in individuals. [Powerpoint File]

Caenorhabditis elegans Muscle: A Genetic and Molecular Model for Protein Interactions in the Heart

Caenorhabditis elegans Muscle: A Genetic and Molecular Model for Protein Interactions in the Heart

Guy M. Benian, Henry F. Epstein

Comparison of normal localization of C elegans twitchin and mouse myosin-binding protein C (MyBP-C). A, C elegans body wall muscle immunostained with antibodies to twitchin. Twitchin is localized to most of the A-band, except for the central portion (indicated by arrow). (Reprinted with permission of Rockefeller University Press from Benian GM, Tinley TL, Tang X, Borodovsky M. The C elegans gene unc-89, required for muscle M-line assembly, encodes a giant modular protein containing Ig and signal transduction domains. J Cell Biology. 1996;132:835–848.) B, Myocardium from a heart of a transgenic mouse expressing myc-tagged MyBP-C, and immunostained with anti-myc. This pattern of localization is similar to localization of endogenous MyBP-C: the protein is localized to much of the A-band, except for the central portion (indicated by arrow). (Reprinted with permission of the American Society for Clinical Investigation from Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J. A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy. J Clin Invest. 1998;102:1292–1300.) [Powerpoint File]