DOCSLIB.ORG

Lamin A/C Mutation Affecting Primarily the Right Side of the Heart

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lamin A/C Mutation Affecting Primarily the Right Side of the Heart Cardiogenetics 2013; volume 3:e1 Lamin A/C mutation affecting right side of the heart. The phenotype resem- bles ARVC but does not fulfill the Task Force Correspondence: Laura Ollila and Tiina Heliö, primarily the right side Criteria. The main clinical manifestations of HYKS/Meilahden sairaala, Sydäntutkimusosasto, of the heart the mutation were severe tricuspid insuffi- PL 340, 00029 HUS, Finland. ciency, right ventricular enlargement and fail- Fax: +358.9.471.74574. Laura Ollila,1 Johanna Kuusisto,2 ure. Three of the affected patients died of the E-mail: [email protected]; [email protected] 2 2 Keijo Peuhkurinen, Satu Kärkkäinen, heart disease, and the two living patients Key words: LMNA, Lamin A/C, dilated cardiomy- Petri Tuomainen,2 Maija Kaartinen,1 received heart transplants at ages 44 and 47. opathy, arrhythmogenic right ventricular car- Olayinka Raheem,3 Bjarne Udd,3,4,5 Electron microscopy showed nuclear blebbing diomyopathy. Jarkko Magga,6 Janne Rapola,1 compatible with laminopathy. Immunohisto - Annukka M. Lahtinen,7 Eero Lehtonen,8,9 chemical analysis did not suggest desmosomal Acknowledgements: we would like to thank Sini Weckström for technical assistance. Miia Holmström,10 Sari Kivistö,10 pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes Elisabeth Widén,11 Markku Saksa,12 Contributions: LO, TH, responsible for all aspects a phenotype different from traditional cardio- Tiina Heliö1 of reliability and freedom from bias of presented laminopathy. Our findings suggest that car- data and their discussed interpretation; JK, 1Helsinki University Hospital, Department diomyopathy affecting primarily the right side genetic analysis, clinical data acquisition and 2 of Cardiology, Helsinki; University of of the heart is not always caused by desmoso- analysis, manuscript revision; KP, PT, MK, JM, JR, Tampere, Tampere; 3Neuromuscular mal pathology. Our observations highlight the MH, SKi, EW, MS, clinical data acquisition and Research Unit, Tampere University and challenges in classifying cardiomyopathies, as analysis, manuscript revision; SKä, AL, genetic University Hospital, Tampere; there often is significant overlap between the analysis, manuscript revision; OR, BU, EL, immunohistochemical analysis of endomyocar- 4Folkhälsan Institute of Genetics and traditional categories. dial samples, manuscript revision. Department of Medical Genetics, Haartman Institute, University of Funding: Finnish Foundation for Cardiovascular Helsinki, Helsinki; 5Neurology Research, Finnish Medical Foundation, Special Department, Vaasa Central Hospital, Introduction governmental subsidy for health sciences onlyresearch, EVO-funds, Finnish Cultural Vaasa; 6Oulu University Hospital, Oulu; Foundation. 7Research Programs Unit, Molecular Idiopathic dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and Medicine and Department of Medicine, Conflict of interests: the authors declare no impaired systolic function in the absence of University of Helsinki, Helsinki; potential conflict of interests. hypertension, coronary artery disease,use valvular 8Department of Pathology, University of disease or other apparent cause. It is estimat- Received for publication: 5 November 2012. Helsinki; 9Laboratory Animal Centre, ed to be hereditary in 25-50% of patients.1-3 Revision received: 15 January 2013. University of Helsinki, Helsinki; Familial DCM has a diverse genetic back- Accepted for publication: 19 January 2013. 10 Department of Radiology, University ground. So far, mutations in more than 40 of Helsinki and HUS Radiology (Medical autosomal genes have been found to cause This work is licensed under a Creative Commons 11 Attribution NonCommercial 3.0 License (CC BY- Imaging Center), Helsinki; Institute for familial DCM in a typically autosomal domi- NC 3.0). Molecular Medicine Finland (FIMM), nant inheritance pattern.3,4 Genes shown to University of Helsinki, Helsinki; cause DCM can be grouped by function or cel- ©Copyright L. Ollila et al., 2013 12Kanta-Häme Central Hospital, lular location into nuclear envelope proteins, Licensee PAGEPress, Italy Hämeenlinna, Finland such as Lamin A/C (LMNA), emerin and Cardiogenetics 2013; 3:e1 nesprin, cytoskeletal proteins such as dys- doi:10.4081/cardiogenetics.2013.e1 commercialtrophin, and sarcomere genes such as - myosin heavy chain and troponin T.3 Using the Abstract traditional Sanger sequencing a genetic cause ent. Carriers of Lamin A/C mutations have also for familial DCM patients can be found in been shown to be at a high risk of ventricular LMNA mutations are amongstNon the most about a third of the cases.5 The proportion of arrhythmias and sudden death.9,10 important causes of familial dilated cardiomy- patients receiving a genetic diagnosis for their Arrhythmogenic right ventricular cardiomy- opathy. The most important cause of arrhyth- disease will likely increase with the use of next opathy (ARVC) affects primarily the right ven- mogenic right ventricular cardiomyopathy generation sequencing techniques as suggest- tricle, although lately biventricular and left (ARVC) is desmosomal pathology. The aim of ed recently by Herman et al. reporting that ventricular forms have been identified.11,12 the study was to elucidate the role of LMNA truncating titin mutations explain approxi- ARVC is characterized by life-threatening mutations among Finnish cardiomyopathy mately 25% of familial DCM.6 arrhythmias and the replacement of the patients. We screened 135 unrelated cardiomy- Lamin A/C has been shown to cause 9% of myocardium with fibro-fatty tissue. It has been opathy patients for LMNA mutations. Because DCM leading to heart transplantation in considered to be caused mainly by mutations of unusual phenotype, two patients were Finland.7 Six Lamin A/C mutations leading to in genes encoding several desmosomal pro- screened for the known Finnish ARVC-related heart disease have been previously reported in teins.13 In addition, non-desmosomal genes mutations of desmosomal genes, and their Finland.7,8 Clinical characteristics most often such as ryanodine receptor 2 (RYR2), trans- Plakophilin-2b gene was sequenced. associated with the Lamin A/C mutations that forming growth factor beta 3 (TGFB3), trans- Myocardial samples from two patients were cause DCM are arrhythmias, in particular atri- membrane protein 43 (TMEM43), and recently examined by immunohistochemical plakoglo- al fibrillation, atrioventricular conduction LMNA, have been associated with ARVC.14-17 bin staining and in one case by electron defects, and bradycardia resulting in a need of Surprisingly, in a population-based cohort of microscopy. We found a new LMNA mutation a pacemaker, left ventricular dilatation and over 6000 Finns, the prevalence of ARVC-relat- Phe237Ser in a family of five affected members eventually heart failure. The onset of clinical ed desmosomal mutations was 1:200 suggest- with a cardiomyopathy affecting primarily the manifestations of the disease is age-depend- ing incomplete penetrance.18 There is signifi- [Cardiogenetics 2013; 3:e1] [page 1] Article cant overlap between the traditional clinical using polymerase chain reaction (PCR). The lead citrate and examined in a Jeol 1400 elec- subtypes of cardiomyopathy. It is not uncom- coding regions of the LMNA gene were directly tron microscope equipped with Olympus-SIS mon for a cardiomyopathy patient to have char- sequenced with ABIPRISM 310 or 3100 Genetic Morada digital camera. acteristics of more than one clinical subtype, analyzer (PE Applied Biosystems, Foster City, Parametric linkage analysis was carried out or change phenotype as the disease progress- CA, USA). The pathogenicity of Lamin A/C in Pedigree 1 by utilizing the software es. The vastly growing genetic knowledge of mutations was assessed in silico using Poly Merlin.23 An affected-only model was used, set- cardiomyopathies also challenges the rigid Phen-2 software.21 ting the disease and marker allele frequencies division of cardiomyopathies in to the classic The genetic analyses of desmosomal pro- to 1/10,000, and considering family-members categories.1,11 teins were performed at the University of with atrioventricular blocks, arrhythmias or In our search for new LMNA mutations in Helsinki. All protein-coding exons and exon- DCM as affected. All participants of the study Finnish cardiomyopathy patients we found intron junctions of plakophilin-2b (PKP2b) signed written informed consent. The study three new mutations and one that has been were amplified using PCR and sequenced with protocol was approved by the Ethics previously reported elsewhere.19 One of the BigDye Terminator v3.1 and ABI 3730xl DNA Committees of the Universities of Helsinki and new mutations is associated with a clinical Analyzer (Applied Biosystems, Carlsbad, CA, Eastern Finland, and is in compliance with the phenotype affecting primarily the right side of USA). All five known Finnish ARVC-associated Helsinki declaration. the heart. Another new mutation is located in mutations plakophilin-2 (PKP2) Q59L, PKP2 the same codon as a previously described Q62K, PKP2 N613K, desmoplakin (DSP) mutation.20 T1373A, and desmoglein-2 (DSG2) 3059_3062delAGAG were assayed using direct Results sequencing or restriction enzyme assays as described previously.18,22 We found one previously reported Lamin A/C Materials and Methods Myocardial samples of the patients III:4 and mutation (Arg166Pro)19 and three new muta- III:6 carrying the LMNA Phe237Ser mutation tions (Phe 237Ser, c.1442 dup A, and We screened
Load more

Recommended publications
  • Cyclin D1/Cyclin-Dependent Kinase 4 Interacts with Filamin a and Affects the Migration and Invasion Potential of Breast Cancer Cells
    Published OnlineFirst February 28, 2010; DOI: 10.1158/0008-5472.CAN-08-1108 Tumor and Stem Cell Biology Cancer Research Cyclin D1/Cyclin-Dependent Kinase 4 Interacts with Filamin A and Affects the Migration and Invasion Potential of Breast Cancer Cells Zhijiu Zhong, Wen-Shuz Yeow, Chunhua Zou, Richard Wassell, Chenguang Wang, Richard G. Pestell, Judy N. Quong, and Andrew A. Quong Abstract Cyclin D1 belongs to a family of proteins that regulate progression through the G1-S phase of the cell cycle by binding to cyclin-dependent kinase (cdk)-4 to phosphorylate the retinoblastoma protein and release E2F transcription factors for progression through cell cycle. Several cancers, including breast, colon, and prostate, overexpress the cyclin D1 gene. However, the correlation of cyclin D1 overexpression with E2F target gene regulation or of cdk-dependent cyclin D1 activity with tumor development has not been identified. This suggests that the role of cyclin D1 in oncogenesis may be independent of its function as a cell cycle regulator. One such function is the role of cyclin D1 in cell adhesion and motility. Filamin A (FLNa), a member of the actin-binding filamin protein family, regulates signaling events involved in cell motility and invasion. FLNa has also been associated with a variety of cancers including lung cancer, prostate cancer, melanoma, human bladder cancer, and neuroblastoma. We hypothesized that elevated cyclin D1 facilitates motility in the invasive MDA-MB-231 breast cancer cell line. We show that MDA-MB-231 motility is affected by disturbing cyclin D1 levels or cyclin D1-cdk4/6 kinase activity.
    [Show full text]
  • 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.
    [Show full text]
  • Plakoglobin Is Required for Effective Intermediate Filament Anchorage to Desmosomes Devrim Acehan1, Christopher Petzold1, Iwona Gumper2, David D
    ORIGINAL ARTICLE Plakoglobin Is Required for Effective Intermediate Filament Anchorage to Desmosomes Devrim Acehan1, Christopher Petzold1, Iwona Gumper2, David D. Sabatini2, Eliane J. Mu¨ller3, Pamela Cowin2,4 and David L. Stokes1,2,5 Desmosomes are adhesive junctions that provide mechanical coupling between cells. Plakoglobin (PG) is a major component of the intracellular plaque that serves to connect transmembrane elements to the cytoskeleton. We have used electron tomography and immunolabeling to investigate the consequences of PG knockout on the molecular architecture of the intracellular plaque in cultured keratinocytes. Although knockout keratinocytes form substantial numbers of desmosome-like junctions and have a relatively normal intercellular distribution of desmosomal cadherins, their cytoplasmic plaques are sparse and anchoring of intermediate filaments is defective. In the knockout, b-catenin appears to substitute for PG in the clustering of cadherins, but is unable to recruit normal levels of plakophilin-1 and desmoplakin to the plaque. By comparing tomograms of wild type and knockout desmosomes, we have assigned particular densities to desmoplakin and described their interaction with intermediate filaments. Desmoplakin molecules are more extended in wild type than knockout desmosomes, as if intermediate filament connections produced tension within the plaque. On the basis of our observations, we propose a particular assembly sequence, beginning with cadherin clustering within the plasma membrane, followed by recruitment of plakophilin and desmoplakin to the plaque, and ending with anchoring of intermediate filaments, which represents the key to adhesive strength. Journal of Investigative Dermatology (2008) 128, 2665–2675; doi:10.1038/jid.2008.141; published online 22 May 2008 INTRODUCTION dense plaque that is further from the membrane and that Desmosomes are large macromolecular complexes that mediates the binding of intermediate filaments.
    [Show full text]
  • Plakophilin-2 Haploinsufficiency Causes Calcium Handling
    International Journal of Molecular Sciences Article Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress Chantal J.M. van Opbergen 1 , Maartje Noorman 1, Anna Pfenniger 2, Jaël S. Copier 1, Sarah H. Vermij 2,3 , Zhen Li 2, Roel van der Nagel 1, Mingliang Zhang 2, Jacques M.T. de Bakker 1,4, Aaron M. Glass 5, Peter J. Mohler 6,7, Steven M. Taffet 5, Marc A. Vos 1, Harold V.M. van Rijen 1, Mario Delmar 2 and Toon A.B. van Veen 1,* 1 Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584CM Utrecht, The Netherlands 2 Division of Cardiology, NYU School of Medicine, New York, NY 10016, USA 3 Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland 4 Department of Medical Biology, Academic Medical Center Amsterdam, 1105AZ Amsterdam, The Netherlands 5 Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA 6 Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA 7 Departments of Physiology & Cell Biology and Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University College of Medicine Wexner Medical Center, Columbus, OH 43210, USA * Correspondence: [email protected] Received: 1 August 2019; Accepted: 19 August 2019; Published: 21 August 2019 Abstract: Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm.
    [Show full text]
  • The Ubiquitin-Proteasome Pathway Mediates Gelsolin Protein Downregulation in Pancreatic Cancer
    The Ubiquitin-Proteasome Pathway Mediates Gelsolin Protein Downregulation in Pancreatic Cancer Xiao-Guang Ni,1 Lu Zhou,2 Gui-Qi Wang,1 Shang-Mei Liu,3 Xiao-Feng Bai,4 Fang Liu,5 Maikel P Peppelenbosch,2 and Ping Zhao4 1Department of Endoscopy, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3Department of Pathology, 4Department of Abdominal Surgery, and 5State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China A well-known observation with respect to cancer biology is that transformed cells display a disturbed cytoskeleton. The under- lying mechanisms, however, remain only partly understood. In an effort to identify possible mechanisms, we compared the pro- teome of pancreatic cancer with matched normal pancreas and observed diminished protein levels of gelsolin—an actin fila- ment severing and capping protein of crucial importance for maintaining cytoskeletal integrity—in pancreatic cancer. Additionally, pancreatic ductal adenocarcinomas displayed substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when compared with cancerous and untransformed tissue from the same patients (P < 0.05). Importantly, no marked downregulation of gelsolin mRNA was observed (P > 0.05), suggesting that post- transcriptional mechanisms mediate low gelsolin protein levels. In apparent agreement, high activity ubiquitin-proteasome path- way in both patient samples and the BxPC-3 pancreatic cancer cell line was detected, and inhibition of the 26s proteasome sys- tem quickly restored gelsolin protein levels in the latter cell line.
    [Show full text]
  • Structural and Biochemical Changes Underlying a Keratoderma-Like Phenotype in Mice Lacking Suprabasal AP1 Transcription Factor Function
    Citation: Cell Death and Disease (2015) 6, e1647; doi:10.1038/cddis.2015.21 OPEN & 2015 Macmillan Publishers Limited All rights reserved 2041-4889/15 www.nature.com/cddis Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function EA Rorke*,1, G Adhikary2, CA Young2, RH Rice3, PM Elias4, D Crumrine4, J Meyer4, M Blumenberg5 and RL Eckert2,6,7,8 Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased.
    [Show full text]
  • INTERMEDIATE FILAMENT Dr Krishnendu Das Assistant Professor Department of Zoology City College
    INTERMEDIATE FILAMENT Dr Krishnendu Das Assistant Professor Department of Zoology City College Q.What are the intermediate filaments? State their role as cytoskeleton. How its functional significance differs from others? This component of cytoskeleton intermediates between actin filaments (about 7 nm in diameter) and microtubules (about 25 nm in diameter). In contrast to actin filament and microtubule the intermediate filaments are not directly involved in cell movements, instead they appear to play basically a structural role by providing mechanical strength to cells and tissues. (Figure 1: Structure of intermediate filament proteins- intermediate filament proteins contain a central α-helical rod domain of approximately 310 amino acids (350 amino acids in the nuclear lamins). The N-terminal head and C-terminal tail domains vary in size and shape. Q.How intermediate filaments differ from actin filaments and microtubules in respect of their components? Actin filaments and microtubules are polymers of single types of proteins (e.g; actin tubulins), whereas intermediate filaments are composed of a variety of proteins that are expressed in different types of cells (as given in the tabular form) Type Protein Size (kd) Site of expression I Acidic keratin 40-60 Epithelial cells II Neutral or basic keratin 50-70 Do III Vimentin 54 Fibroblasts, WBC and other cell types Desmin 53 Muscle cells Periferin 57 Peripheral neurons IV Neurofilament proteins NF-L 67 Neurons NF-M 150 Neurons NF-H 200 Neurons V Nuclear lamins 60-75 Nuclear lamina of all cell types VI nestin 200 Stem cells, especially of the central nervous system Q.How do intermediate filaments assemble? (Figure 2) The central rod domains of two polypeptides wind around each other in a coiled-coil structure to form dimmers.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Electrophoresis
    ELECTROPHORESIS Supporting Information for Electrophoresis DOI 10.1002/elps.200700936 Qiaozhen Lu, Nivetha Murugesan, Jennifer A. Macdonald, Shiaw-Lin Wu, Joel S. Pachter and William S. Hancock Analysis of mouse brain microvascular endothelium using immuno-laser capture microdissection coupled to a hybrid LTQ-FT-MS proteomics platform ª 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.electrophoresis-journal.com Table A. List of total proteins identified in CD31 immunostained LCM Sample Protein name Peptide (Hits) Coverag MW Accession (%) # keratin complex 1, acidic, gene 14 [Mus musculus] 15 (15 0 0 0 0) 2.56E+01 52866.70 21489935 neurofilament, light polypeptide [Mus musculus] 4 (4 0 0 0 0) 6.10E+00 61507.96 39204499 actin, beta, cytoplasmic [Mus musculus] 21 (21 0 0 0 0) 3.36E+01 41736.51 6671509 ATP synthase, H+ transporting, mitochondrial F1 complex, alpha 11 (11 0 0 0 0) 2.03E+01 59752.23 6680748 subunit, isoform 1 [Mus musculus] vesicle-associated membrane protein 2 [Mus musculus] 4 (4 0 0 0 0) 3.45E+01 12690.70 6678551 tubulin, beta 6 [Mus musculus] 1 (1 0 0 0 0) 4.00E+00 50090.05 27754056 actin-like [Mus musculus] 2 (2 0 0 0 0) 5.60E+00 43600.63 8850209 hemoglobin alpha 1 chain [Mus musculus] 3 (3 0 0 0 0) 2.39E+01 15085.06 6680175 keratinocyte associated protein 1 [Mus musculus] 23 (23 0 0 0 0) 1.22E+01 59740.13 29789317 ATP synthase, H+ transporting mitochondrial F1 complex, beta 18 (18 0 0 0 0) 4.03E+01 56300.11 31980648 subunit [Mus musculus] tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 3 (3 0 0 0 0) 1.80E+01 27770.96
    [Show full text]
  • De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe
    International Journal of Molecular Sciences Article De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents Roua Hassoun 1,2, Heidi Budde 1,2, Hans Georg Mannherz 1,3,Mária Lódi 4 , Setsuko Fujita-Becker 5, Kai Thorsten Laser 6, Anna Gärtner 7 , Karin Klingel 8 , Desirée Möhner 9, Robert Stehle 9, Innas Sultana 1,2, Thomas Schaaf 1,2 , Mario Majchrzak 1,2, Verena Krause 1,2, Christian Herrmann 10, Marc M. Nowaczyk 11, Andreas Mügge 1,2, Gabriele Pfitzer 9, Rasmus R. Schröder 5, Nazha Hamdani 1,2, Hendrik Milting 7, Kornelia Jaquet 1,2,*,† and Diana Cimiotti 1,2,12,*,† 1 Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany; [email protected] (R.H.); [email protected] (H.B.); [email protected] (H.G.M.); [email protected] (I.S.); [email protected] (T.S.); [email protected] (M.M.); [email protected] (V.K.); [email protected] (A.M.); [email protected] (N.H.) 2 Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany 3 Department of Anatomy and Molecular Embryology, Ruhr University Bochum, 44801 Bochum, Germany 4 Department of Neuroanatomy and Molecular Brain Research, Medical Faculty, Ruhr University Bochum, Citation: Hassoun, R.; Budde, H.; 44801 Bochum, Germany; [email protected] Mannherz, H.G.; Lódi, M.; 5 Cryoelectron Microscopy, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany; Fujita-Becker, S.; Laser, K.T.; Gärtner, [email protected] (S.F.-B.); A.; Klingel, K.; Möhner, D.; Stehle, R.; [email protected] (R.R.S.) 6 Centre for Congenital Heart Disease/Pediatric Cardiology, Heart and Diabetes Centre NRW, University et al.
    [Show full text]
  • The Transcription Factor Snail Induces Tumor Cell Invasion Through Modulation of the Epithelial Cell Differentiation Program
    Research Article The Transcription Factor Snail Induces Tumor Cell Invasion through Modulation of the Epithelial Cell Differentiation Program Bram De Craene,1 Barbara Gilbert,1 Christophe Stove,1,2 Erik Bruyneel,3 Frans van Roy,2 and Geert Berx1 1Unit of Molecular and Cellular Oncology and 2Molecular Cell Biology Unit, Department for Molecular Biomedical Research, VIB-Ghent University; and 3Laboratory of Experimental Cancerology, University Hospital of Ghent, Ghent, Belgium Abstract studies have focused on the global effects of Snail transcriptional activity, and information on the early response genes in cells Abberant activation of the process of epithelial-mesenchymal transition in cancer cells is a late event in tumor progression. expressing Snail is limited. Here, we show that conditional A key inducer of this transition is the transcription factor expression of human Snail (hSnail) in human colon cancer cells Snail, which represses E-cadherin. We report that conditional promotes an epithelial-mesenchymal transition–like process in expression of the human transcriptional repressor Snail in which loss of intercellular adhesion coincides with induction of colorectal cancer cells induces an epithelial dedifferentiation invasiveness. To identify transcriptional changes that are specific program that coincides with a drastic change in cell responses toward hSnail expression, a comparative differential morphology. Snail target genes control the establishment of gene expression analysis using cDNA microarrays was done. This several junctional complexes, intermediate filament networks, molecular functional analysis revealed that Snail induction leads to and the actin cytoskeleton. Modulation of the expression of a general (de)regulation of epithelial differentiation, metabolism, and signal transduction. Using chromatin immunoprecipitation, we these genes is associated with loss of cell aggregation and induction of invasion.
    [Show full text]
  • Clinical and Genetic Issues in Dilated Cardiomyopathy: a Review for Genetics Professionals Ray E
    REVIEW Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals Ray E. Hershberger, MD, Ana Morales, MS, CGC, and Jill D. Siegfried, MS, CGC Abstract: Dilated cardiomyopathy (DCM), usually diagnosed as idio- based on four key facts. First, DCM of all causes underlies at pathic dilated cardiomyopathy (IDC), has been shown to have a familial least half of the heart failure epidemic in the United States, basis in 20–35% of cases. Genetic studies in familial dilated cardiomy- where the heart failure syndrome is defined as an inadequate opathy (FDC) have shown dramatic locus heterogeneity with mutations cardiac output to provide circulatory and nutrient support to the identified in Ͼ30 mostly autosomal genes showing primarily dominant body. Heart failure, from American Heart Association statistics in 2 transmission. Most mutations are private missense, nonsense or short 2010, affected approximately 5.8 million US citizens, of which a insertion/deletions. Marked allelic heterogeneity is the rule. Although to significant portion will be diagnosed with DCM of unknown cause date most DCM genetics fits into a Mendelian rare variant disease (otherwise characterized as idiopathic DCM [IDC]). Second, a paradigm, this paradigm may be incomplete with only 30–35% of FDC genetic cause has been demonstrated for an estimated 30–35% of genetic cause identified. Despite this incomplete knowledge, we predict IDC (in familial or apparently sporadic cases), making testing that DCM genetics will become increasingly relevant for genetics and feasible. Third, the recent dramatic progress with more cost- cardiovascular professionals. This is because DCM causes heart failure, effective genetic testing makes predictive diagnosis possible a national epidemic, with considerable morbidity and mortality.
    [Show full text]