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Christine seidman

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https://www.readbyqxmd.com/read/27895300/thsd1-thrombospondin-type-1-domain-containing-protein-1-mutation-in-the-pathogenesis-of-intracranial-aneurysm-and-subarachnoid-hemorrhage
#1
Teresa Santiago-Sim, Xiaoqian Fang, Morgan L Hennessy, Stephen V Nalbach, Steven R DePalma, Ming Sum Lee, Steven C Greenway, Barbara McDonough, Georgene W Hergenroeder, Kyla J Patek, Sarah M Colosimo, Krista J Qualmann, John P Hagan, Dianna M Milewicz, Calum A MacRae, Susan M Dymecki, Christine E Seidman, J G Seidman, Dong H Kim
BACKGROUND AND PURPOSE: A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease. METHODS: More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls...
December 2016: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/27869827/titin-truncating-variants-affect-heart-function-in-disease-cohorts-and-the-general-population
#2
Sebastian Schafer, Antonio de Marvao, Eleonora Adami, Lorna R Fiedler, Benjamin Ng, Ester Khin, Owen J L Rackham, Sebastiaan van Heesch, Chee J Pua, Miao Kui, Roddy Walsh, Upasana Tayal, Sanjay K Prasad, Timothy J W Dawes, Nicole S J Ko, David Sim, Laura L H Chan, Calvin W L Chin, Francesco Mazzarotto, Paul J Barton, Franziska Kreuchwig, Dominique P V de Kleijn, Teresa Totman, Carlo Biffi, Nicole Tee, Daniel Rueckert, Valentin Schneider, Allison Faber, Vera Regitz-Zagrosek, Jonathan G Seidman, Christine E Seidman, Wolfgang A Linke, Jean-Paul Kovalik, Declan O'Regan, James S Ware, Norbert Hubner, Stuart A Cook
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27831900/aggregate-penetrance-of-genomic-variants-for-actionable-disorders-in-european-and-african-americans
#3
Pradeep Natarajan, Nina B Gold, Alexander G Bick, Heather McLaughlin, Peter Kraft, Heidi L Rehm, Gina M Peloso, James G Wilson, Adolfo Correa, Jonathan G Seidman, Christine E Seidman, Sekar Kathiresan, Robert C Green
In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs...
November 9, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27806233/fulminant-myocarditis-with-combination-immune-checkpoint-blockade
#4
Douglas B Johnson, Justin M Balko, Margaret L Compton, Spyridon Chalkias, Joshua Gorham, Yaomin Xu, Mellissa Hicks, Igor Puzanov, Matthew R Alexander, Tyler L Bloomer, Jason R Becker, David A Slosky, Elizabeth J Phillips, Mark A Pilkinton, Laura Craig-Owens, Nina Kola, Gregory Plautz, Daniel S Reshef, Jonathan S Deutsch, Raquel P Deering, Benjamin A Olenchock, Andrew H Lichtman, Dan M Roden, Christine E Seidman, Igor J Koralnik, Jonathan G Seidman, Robert D Hoffman, Janis M Taube, Luis A Diaz, Robert A Anders, Jeffrey A Sosman, Javid J Moslehi
Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates...
November 3, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27670201/loss-of-rna-expression-and-allele-specific-expression-associated-with-congenital-heart-disease
#5
David M McKean, Jason Homsy, Hiroko Wakimoto, Neil Patel, Joshua Gorham, Steven R DePalma, James S Ware, Samir Zaidi, Wenji Ma, Nihir Patel, Richard P Lifton, Wendy K Chung, Richard Kim, Yufeng Shen, Martina Brueckner, Elizabeth Goldmuntz, Andrew J Sharp, Christine E Seidman, Bruce D Gelb, J G Seidman
Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects...
September 27, 2016: Nature Communications
https://www.readbyqxmd.com/read/27582060/pitx2-modulates-a-tbx5-dependent-gene-regulatory-network-to-maintain-atrial-rhythm
#6
Rangarajan D Nadadur, Michael T Broman, Bastiaan Boukens, Stefan R Mazurek, Xinan Yang, Malou van den Boogaard, Jenna Bekeny, Margaret Gadek, Tarsha Ward, Min Zhang, Yun Qiao, James F Martin, Christine E Seidman, Jon Seidman, Vincent Christoffels, Igor R Efimov, Elizabeth M McNally, Christopher R Weber, Ivan P Moskowitz
Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice...
August 31, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27505173/transcriptional-profiling-of-cultured-embryonic-epicardial-cells-identifies-novel-genes-and-signaling-pathways-regulated-by-tgf%C3%AE-r3-in-vitro
#7
Daniel M DeLaughter, Cynthia R Clark, Danos C Christodoulou, Christine E Seidman, H Scott Baldwin, J G Seidman, Joey V Barnett
The epicardium plays an important role in coronary vessel formation and Tgfbr3-/- mice exhibit failed coronary vessel development associated with decreased epicardial cell invasion. Immortalized Tgfbr3-/- epicardial cells display the same defects. Tgfbr3+/+ and Tgfbr3-/- cells incubated for 72 hours with VEH or ligands known to promote invasion via TGFβR3 (TGFβ1, TGFβ2, BMP2), for 72 hours were harvested for RNA-seq analysis. We selected for genes >2-fold differentially expressed between Tgfbr3+/+ and Tgfbr3-/- cells when incubated with VEH (604), TGFβ1 (515), TGFβ2 (553), or BMP2 (632)...
2016: PloS One
https://www.readbyqxmd.com/read/27366888/detection-of-cell-proliferation-markers-by-immunofluorescence-staining-and-microscopy-imaging-in-paraffin-embedded-tissue-sections
#8
Seda Eminaga, Polakit Teekakirikul, Christine E Seidman, Jonathan G Seidman
This unit describes a step-by-step protocol to detect and quantify proliferating cells in paraffin-embedded tissue sections. Two well-established markers of proliferation (incorporation of BrdU into newly synthesized DNA and expression of the nuclear protein Ki67) are detected after antigen-retrieval and subsequent immunofluorescence staining and confocal microscopy. © 2016 by John Wiley & Sons, Inc.
2016: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/27239561/molecular-profiling-of-dilated-cardiomyopathy-that-progresses-to-heart-failure
#9
Michael A Burke, Stephen Chang, Hiroko Wakimoto, Joshua M Gorham, David A Conner, Danos C Christodoulou, Michael G Parfenov, Steve R DePalma, Seda Eminaga, Tetsuo Konno, Jonathan G Seidman, Christine E Seidman
Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLN(R9C/+)). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10(-4)) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3...
May 5, 2016: JCI Insight
https://www.readbyqxmd.com/read/27189347/corrigendum-mutation-analysis-of-the-phospholamban-gene-in-315-south-africans-with-dilated-hypertrophic-peripartum-and-arrhythmogenic-right-ventricular-cardiomyopathies
#10
Maryam Fish, Gasnat Shaboodien, Sarah Kraus, Karen Sliwa, Christine E Seidman, Michael A Burke, Lia Crotti, Peter J Schwartz, Bongani M Mayosi
No abstract text is available yet for this article.
2016: Scientific Reports
https://www.readbyqxmd.com/read/27114035/a-tension-based-model-distinguishes-hypertrophic-versus-dilated-cardiomyopathy
#11
Jennifer Davis, L Craig Davis, Robert N Correll, Catherine A Makarewich, Jennifer A Schwanekamp, Farid Moussavi-Harami, Dan Wang, Allen J York, Haodi Wu, Steven R Houser, Christine E Seidman, Jonathan G Seidman, Michael Regnier, Joseph M Metzger, Joseph C Wu, Jeffery D Molkentin
The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth...
May 19, 2016: Cell
https://www.readbyqxmd.com/read/26920199/the-muscle-bound-heart
#12
REVIEW
Marwan M Refaat, Akl C Fahed, Sylvana Hassanieh, Mostafa Hotait, Mariam Arabi, Hadi Skouri, Jonathan G Seidman, Christine E Seidman, Fadi F Bitar, Georges Nemer
Hypertrophic cardiomyopathy (HCM) is a familial cardiac disease manifested in a wide phenotype and diverse genotype and, thus, presenting unpredictable risks mainly on young adults. Extensive studies are being conducted to categorize patients and link phenotype with genotype for a better management and control of the disease with all its complications. Because the full mechanisms behind HCM are still not revealed, therapeutics are not definitive. Further research is to be conducted for the generation of a complete picture and directed therapy for HCM...
March 2016: Cardiac Electrophysiology Clinics
https://www.readbyqxmd.com/read/26917049/mutation-analysis-of-the-phospholamban-gene-in-315-south-africans-with-dilated-hypertrophic-peripartum-and-arrhythmogenic-right-ventricular-cardiomyopathies
#13
Maryam Fish, Gasnat Shaboodien, Sarah Kraus, Karen Sliwa, Christine E Seidman, Michael A Burke, Lia Crotti, Peter J Schwartz, Bongani M Mayosi
Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown...
2016: Scientific Reports
https://www.readbyqxmd.com/read/26912705/a-small-molecule-inhibitor-of-sarcomere-contractility-suppresses-hypertrophic-cardiomyopathy-in-mice
#14
Eric M Green, Hiroko Wakimoto, Robert L Anderson, Marc J Evanchik, Joshua M Gorham, Brooke C Harrison, Marcus Henze, Raja Kawas, Johan D Oslob, Hector M Rodriguez, Yonghong Song, William Wan, Leslie A Leinwand, James A Spudich, Robert S McDowell, J G Seidman, Christine E Seidman
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain...
February 5, 2016: Science
https://www.readbyqxmd.com/read/26785492/de-novo-mutations-in-congenital-heart-disease-with-neurodevelopmental-and-other-congenital-anomalies
#15
Jason Homsy, Samir Zaidi, Yufeng Shen, James S Ware, Kaitlin E Samocha, Konrad J Karczewski, Steven R DePalma, David McKean, Hiroko Wakimoto, Josh Gorham, Sheng Chih Jin, John Deanfield, Alessandro Giardini, George A Porter, Richard Kim, Kaya Bilguvar, Francesc López-Giráldez, Irina Tikhonova, Shrikant Mane, Angela Romano-Adesman, Hongjian Qi, Badri Vardarajan, Lijiang Ma, Mark Daly, Amy E Roberts, Mark W Russell, Seema Mital, Jane W Newburger, J William Gaynor, Roger E Breitbart, Ivan Iossifov, Michael Ronemus, Stephan J Sanders, Jonathan R Kaltman, Jonathan G Seidman, Martina Brueckner, Bruce D Gelb, Elizabeth Goldmuntz, Richard P Lifton, Christine E Seidman, Wendy K Chung
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing...
December 4, 2015: Science
https://www.readbyqxmd.com/read/26735901/shared-genetic-predisposition-in-peripartum-and-dilated-cardiomyopathies
#16
James S Ware, Jian Li, Erica Mazaika, Christopher M Yasso, Tiffany DeSouza, Thomas P Cappola, Emily J Tsai, Denise Hilfiker-Kleiner, Chizuko A Kamiya, Francesco Mazzarotto, Stuart A Cook, Indrani Halder, Sanjay K Prasad, Jessica Pisarcik, Karen Hanley-Yanez, Rami Alharethi, Julie Damp, Eileen Hsich, Uri Elkayam, Richard Sheppard, Angela Kealey, Jeffrey Alexis, Gautam Ramani, Jordan Safirstein, John Boehmer, Daniel F Pauly, Ilan S Wittstein, Vinay Thohan, Mark J Zucker, Peter Liu, John Gorcsan, Dennis M McNamara, Christine E Seidman, Jonathan G Seidman, Zoltan Arany
Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls...
January 21, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/26436652/cardiomyocyte-enriched-protein-cip-protects-against-pathophysiological-stresses-and-regulates-cardiac-homeostasis
#17
Zhan-Peng Huang, Masaharu Kataoka, Jinghai Chen, Gengze Wu, Jian Ding, Mao Nie, Zhiqiang Lin, Jianming Liu, Xiaoyun Hu, Lixin Ma, Bin Zhou, Hiroko Wakimoto, Chunyu Zeng, Jan Kyselovic, Zhong-Liang Deng, Christine E Seidman, J G Seidman, William T Pu, Da-Zhi Wang
Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy...
November 2, 2015: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/26381200/a-clinical-approach-to-elimination-of-perinatal-hiv-transmission-in-resource-rich-settings
#18
Dominika Seidman, Theodore Ruel, Lisa Rahangdale, Pooja Mittal, Christine Pecci, Shannon Weber, Ronald Goldschmidt, Deborah Cohan, Judy Levison
No abstract text is available yet for this article.
December 2015: International Journal of Gynaecology and Obstetrics
https://www.readbyqxmd.com/read/26315439/heart-disease-titin-mutations-in-ips-cells-define-sarcomere-insufficiency-as-a-cause-of-dilated-cardiomyopathy
#19
John T Hinson, Anant Chopra, Navid Nafissi, William J Polacheck, Craig C Benson, Sandra Swist, Joshua Gorham, Luhan Yang, Sebastian Schafer, Calvin C Sheng, Alireza Haghighi, Jason Homsy, Norbert Hubner, George Church, Stuart A Cook, Wolfgang A Linke, Christopher S Chen, J G Seidman, Christine E Seidman
Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated...
August 28, 2015: Science
https://www.readbyqxmd.com/read/26153423/cardiac-myosin-binding-protein-c-regulates-postnatal-myocyte-cytokinesis
#20
Jianming Jiang, Patrick G Burgon, Hiroko Wakimoto, Kenji Onoue, Joshua M Gorham, Caitlin C O'Meara, Gregory Fomovsky, Bradley K McConnell, Richard T Lee, J G Seidman, Christine E Seidman
Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity...
July 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
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