DOCSLIB.ORG

Mutations in MYOZ1 As Well As MYOZ2 Encoding

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mutations in MYOZ1 As Well As MYOZ2 Encoding Molecular Genetics and Metabolism 91 (2007) 207–208 www.elsevier.com/locate/ymgme Letter to the Editor Mutations in MYOZ1 as well as MYOZ2 encoding the (as described here) the probability that the respective calsarcins are not associated with idiopathic and familial candidate gene does not constitute a relevant disease gene dilated cardiomyopathy is higher when screening a cohort with familial disease. The most important point to address to the work de- Dear Editor, scribed by Arola et al. [1] is that the analysis should not be restricted to MYOZ1 when investigating the genetic eti- We have read the article of Arola and colleagues [1] with ology of DCM. Indeed, MYOZ1 is abundantly expressed great interest. The authors report a candidate gene in skeletal muscle, but cardiomyocytes reveal a very weak approach in the MYOZ1 gene encoding calsarcin-2 in mRNA expression of MYOZ1 [5]. Conversely, MYOZ2 185 patients with idiopathic dilated cardiomyopathy encoding calsarcin-1 is predominantly expressed in cardio- (iDCM). No disease associated mutation was identified myocytes and to lesser extends in skeletal muscle [5,6]. by use of denaturing high-performance liquid chromatog- Calsarcin-1 is located at the sarcomeric Z-disk and inter- raphy (DHPLC). acts with DCM disease genes like telethonin and a-actinin. We have examined a cohort of 61 patients with proven Furthermore, conditional MYOZ2 knock out mice reveal familial dilated cardiomyopathy (fDCM). fDCM was diag- heart failure and extensive dilation of both ventricles after nosed when two or more affected relatives were present in aortic banding [7]. Therefore, MYOZ2 represents a more one family (range: 2–7; mean: 3.2). Clinical examination plausible candidate gene for DCM. was performed according to the European guidelines for However, taking together the results from Arola et al. investigation of familial dilated cardiomyopathy [2] as de- [1] with results from a recent candidate gene approach ana- scribed previously [3]. We directly sequenced all coding lyzing MYOZ2 [8], pathogenic mutations in MYOZ1 and exons (2–6) with flanking intronic portions of MYOZ1 MYOZ2 could not be identified in 185 and 19 patients with by use of ABI Big Dye chemistry as described in detail in idiopathic DCM patients, respectively. Additionally, we [4]. In contrast to Arola et al. [1], we additionally analyzed have excluded mutations in both genes in a cohort of 61 exonic fragments (2–6) of MYOZ2 encoding the cardiac carefully selected families with fDCM using a highly sensi- calsarcin-1. tive screening method. We also identified the L255L (CTG > CTT) variant as In conclusion, one can state that mutations in MYOZ1 described in [1]. Five fDCM patients were heterozygous and MYOZ2 are at least very rare events as an underlying L255L carriers. However, no other genetic variant in disease mechanism for idiopathic or familial DCM. MYOZ1 could be detected by us. Sequencing of MYOZ2 We acknowledge the support of the Berlin Institute for resulted in identification of two synonymous polymor- Heart Research (BIHR-VH-VI 152) funded by the Helm- phisms (A79A and E153E). These heterozygous variants holtz Gemeinschaft, research grant from Charite´-Universi- were uniquely detected in two individuals with fDCM. ta¨tsmedizin Berlin and the German Heart Failure Network All identified polymorphisms in MYOZ1 and MYOZ2 (GHFN). are represented in Fig. 1. Although DHPLC has been proven to be a sensitive References method for mutational analysis, one can not completely ex- clude that some variants might have escaped the analysis of [1] A.M. Arola, X. Sanchez, R.T. Murphy, E. Hasle, H. Li, P.M. Elliot, Arola and colleagues. However, direct sequencing consti- W.J. McKenna, J.A. Towbin, N.E. Bowles, Mutations in PDLIM3 and MYOZ1 encoding myocyte Z line proteins are infrequently found tutes the gold standard of genetic analysis almost excluding in idiopathic dilated cardiomyopathy, Mol. Genet. Metab. (2007), false negative results in candidate gene approaches. Fur- doi:10.1016/j.ymgme.2006.12.008. thermore, screening in patients with a hereditary form of [2] L. Mestroni, B. Maisch, W.J. McKenna, K. Schwartz, P. Charron, C. DCM offers several advantages: first, the prevalence of Rocco, F. Tesson, A. Richter, A. Wilke, M. Komajda, Guidelines for pathogenic mutations should be higher in patients with the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on familial DCM. Further, identified unknown variants can Familial Dilated Cardiomyopathy, Eur. Heart J. 20 (1999) 93–102. easily be checked for co-segregation with the disease in [3] A. Perrot, H.H. Sigusch, H. Nagele, J. Genschel, H.B. Lehmkuhl, R. the family pedigrees. Secondly, in case of negative results Hetzer, C. Geier, V. Leon Perez, D. Reinhard, R. Dietz, K.J. Osterziel, 1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.02.014 208 Letter to the Editor / Molecular Genetics and Metabolism 91 (2007) 207–208 [4] C. Geier, A. Perrot, C. Ozcelik, P. Binner, D. Counsell, K. Hoffmann, MYOZ1 (Calsarcin-2) a B. Pilz, Y. Martiniak, K. Gehmlich, P.F. van der Ven, D.O. Furst, A. S50S L255L Vornwald, E. von Hodenberg, P. Nurnberg, T. Scheffold, R. Dietz, K.J. Osterziel, Mutations in the human muscle LIM protein gene in bp 347 91 179 250 166 508 families with hypertrophic cardiomyopathy, Circulation 107 (2003) 1390–1395. 1 2 3 4 5 6 [5] G. Faulkner, A. Pallavicini, A. Comelli, M. Salamon, G. Bortoletto, C. Ievolella, S. Trevisan, S. Kojic, F. Dalla Vecchia, P. Laveder, G. Valle, G. Lanfranchi, FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle, J. Biol. Chem. 275 (2000) 41234–41242. [6] N. Frey, J.A. Richardson, E.N. Olson, Calsarcins, a novel family of NH2 COOH sarcomeric calcineurin-binding proteins, Proc. Natl. Acad. Sci. USA 97 aa 1 75 171 299 (2000) 14632–14637. telethonin α-actinin myotilin [7] N. Frey, T. Barrientos, J.M. Shelton, D. Frank, H. Rutten, D. filaminC filamin C Gehring, C. Kuhn, M. Lutz, B. Rothermel, R. Bassel-Duby, J.A. Richardson, H.A. Katus, J.A. Hill, E.N. Olson, Mice lacking calsarcin- b MYOZ2 (Calsarcin-1) 1 are sensitized to calcineurin signaling and show accelerated cardio- A79A c.246-18A>G E153E myopathy in response to pathological biomechanical stress, Nat. Med. (rs17851524) (rs11721566) (rs7687613) 12 (2004) 1336–1343. [8] R. Zeller, B.T. Ivandic, P. Ehlermann, O. Mucke, C. Zugck, A. bp 117 76 170 130 184 1815 Remppis, E. Giannitsis, H.A. Katus, D. Weichenhan, Large-scale 1 2 3 4 5 6 mutation screening in patients with dilated or hypertrophic cardio- myopathy: a pilot study using DGGE, J. Mol. Med. 84 (2006) 682–691. Maximilian G. Posch* Andreas Perrot NH2 COOH Rainer Dietz aa 1 153 200 217 240 264 Cemil O¨ zcelik telethonin α-actinin calcineurin Charite´ – Universita¨tsmedizin Berlin/Cardiology at Campus calcineurin filamin C Buch & Virchow Klinikum, Helios-Kliniken and Fig. 1. Schematic representation of the gene structure of MYOZ1 Max-Delbru¨ck Center for Molecular Medicine, (NM_021245) encoding calsarcin-2 and MYOZ2 (NM_016599) encoding Wiltbergstrasse 50, 13125 Berlin, Germany calsarcin-1 with the variants identified by Arola et al. [1] and us indicated. E-mail address: [email protected] Open boxes represent exons with the number of coding nucleotides above (M.G. Posch). and UTRs shaded. The S50S variant in MYOZ1 was described by Arola et al. [1], whereas the L255L variant in MYOZ1 was identified by Arola Sabine Pankuweit et al. and us (allelic frequency 8.2%). The A79A and E153E polymor- Volker Ruppert phisms in MYOZ2 were identified in two patients of our fDCM cohort, respectively. Many different and overlapping protein–protein interaction Anette Richter domains have been described for calsarcin-1 and calsarcin-2 in different Bernhard Maisch studies [5,6]. Department of Internal Medicine and Cardiology, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany H.H. Schmidt, Genetic and phenotypic analysis of dilated cardiomy- opathy with conduction system disease: demand for strategies in the management of presymptomatic lamin A/C mutant carriers, Eur. J. Received 26 February 2007; accepted 26 February 2007 Heart Fail. 8 (2006) 484–493. Available online 16 April 2007 * Corresponding author. Fax: +49 30 9417 2279. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。 学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源， 提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。 图书馆致力于便利、促进学习与科研，提供最强文献下载服务。 图书馆导航： 图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具.
Load more

Recommended publications
  • 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.
    [Show full text]
  • RNA Sequencing Reveals a Slow to Fast Muscle Fiber Type Transition After Olanzapine Infusion in Rats
    RESEARCH ARTICLE RNA Sequencing Reveals a Slow to Fast Muscle Fiber Type Transition after Olanzapine Infusion in Rats Christopher J. Lynch1*, Yuping Xu1, Andras Hajnal2, Anna C. Salzberg3, Yuka Imamura Kawasawa4,5,6 1 Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 2 Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 3 Department a11111 of Public Health Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 4 Department of Pharmacology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 5 Department of Biochemistry and Molecular Biology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 6 The Institute for Personalized Medicine, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America * [email protected] OPEN ACCESS Citation: Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI (2015) RNA Sequencing Reveals a Abstract Slow to Fast Muscle Fiber Type Transition after Olanzapine Infusion in Rats. PLoS ONE 10(4): Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side ef- e0123966. doi:10.1371/journal.pone.0123966 fects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understand- Academic Editor: Guillermo López Lluch, ing how SGAs affect the skeletal muscle transcriptome could elucidate approaches for Universidad Pablo de Olavide, Centro Andaluz de mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with ve- Biología del Desarrollo-CSIC, SPAIN hicle or olanzapine for 24h using a dose leading to a mild hyperglycemia.
    [Show full text]
  • Anti-MYOZ2 (GW22350F)
    3050 Spruce Street, Saint Louis, MO 63103 USA Tel: (800) 521-8956 (314) 771-5765 Fax: (800) 325-5052 (314) 771-5757 email: [email protected] Product Information Anti-MYOZ2 antibody produced in chicken, affinity isolated antibody Catalog Number GW22350F Formerly listed as GenWay Catalog Number 15-288-22350F, Myozenin-2 Antibody. – Storage Temperature Store at 20 °C The product is a clear, colorless solution in phosphate buffered saline, pH 7.2, containing 0.02% sodium azide. Synonyms: Myozenin 2, Calsarcin-1; FATZ-related protein 2 Species Reactivity: Human Product Description Myozenins may serve as intracellular binding proteins Tested Applications: WB involved in linking Z-disk proteins such as alpha-actinin. Recommended Dilutions: Recommended starting dilution gamma-filamin. TCAP/telethonin. LDB3/ZASP and localizing for Western blot analysis is 1:500, for tissue or cell staining calcineurin signaling to the sarcomere. Plays an important 1:200. role in the modulation of calcineurin signaling. May play a role in myofibrillogenesis. Note: Optimal concentrations and conditions for each application should be determined by the user. NCBI Accession number: NP_057683.1 Swiss Prot Accession number: Q9NPC6 Precautions and Disclaimer This product is for R&D use only, not for drug, household, or Gene Information: Human .. MYOZ2 (51778) other uses. Due to the sodium azide content a material Immunogen: Recombinant protein Myozenin 2 safety data sheet (MSDS) for this product has been sent to the attention of the safety officer of your institution. Please Immunogen Sequence: GI # 7706595, sequence 1 - 264 consult the Material Safety Data Sheet for information regarding hazards and safe handling practices.
    [Show full text]
  • Mutations in MYOZ1 As Well As MYOZ2 Encoding the Calsarcins Are Not Associated with Idiopathic and Familial Dilated Cardiomyopathy
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by MDC Repository Repository of the Max Delbrück Center for Molecular Medicine (MDC) Berlin (Germany) http://edoc.mdc-berlin.de/8815/ Mutations in MYOZ1 as well as MYOZ2 encoding the calsarcins are not associated with idiopathic and familial dilated cardiomyopathy Maximilian G. Posch, Andreas Perrot, Rainer Dietz, Cemil Özcelik, Sabine Pankuweit, Volker Ruppert, Anette Richter, and Bernhard Maisch Published in final edited form as: Molecular Genetics and Metabolism. 2007 Jun; 91(2): 207-208 doi: 10.1016/j.ymgme.2007.02.014 Elsevier (The Netherlands) ► Letter to the editor Mutations in MYOZ1 as well as MYOZ2 encoding the calsarcins are not associated with idiopathic and familial dilated cardiomyopathy Maximilian G. Posch, Andreas Perrot, Rainer Dietz, Cemil Özcelik, Sabine Pankuweit, Volker Ruppert, Anette Richter, and Bernhard Maisch 1 Charité – Universitätsmedizin Berlin/Cardiology at Campus Buch & Virchow Klinikum, Helios-Kliniken and Max- Delbrück Center for Molecular Medicine, Wiltbergstrasse 50, 13125 Berlin, Germany 2 Department of Internal Medicine and Cardiology, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany a very weak mRNA expression of MYOZ1 [5]. Conversely, Dear Editor, MYOZ2 encoding calsarcin-1 is predominantly expressed We have read the article of Arola and colleagues [1] with in cardiomyocytes and to lesser extends in skeletal great interest. The authors report a candidate gene muscle [5,6]. Calsarcin-1 is located at the sarcomeric Z- approach in the MYOZ1 gene encoding calsarcin-2 in 185 disk and interacts with DCM disease genes like telethonin patients with idiopathic dilated cardiomyopathy (iDCM).
    [Show full text]
  • Myozenin 1 (MYOZ1) (NM 021245) Human Recombinant Protein Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TP306448 Myozenin 1 (MYOZ1) (NM_021245) Human Recombinant Protein Product data: Product Type: Recombinant Proteins Description: Recombinant protein of human myozenin 1 (MYOZ1) Species: Human Expression Host: HEK293T Tag: C-Myc/DDK Predicted MW: 31.6 kDa Concentration: >50 ug/mL as determined by microplate BCA method Purity: > 80% as determined by SDS-PAGE and Coomassie blue staining Buffer: 25 mM Tris.HCl, pH 7.3, 100 mM glycine, 10% glycerol Preparation: Recombinant protein was captured through anti-DDK affinity column followed by conventional chromatography steps. Storage: Store at -80°C. Stability: Stable for 12 months from the date of receipt of the product under proper storage and handling conditions. Avoid repeated freeze-thaw cycles. RefSeq: NP_067068 Locus ID: 58529 UniProt ID: Q9NP98 RefSeq Size: 1583 Cytogenetics: 10q22.2 RefSeq ORF: 897 Synonyms: CS-2; FATZ; MYOZ Summary: The protein encoded by this gene is primarily expressed in the skeletal muscle, and belongs to the myozenin family. Members of this family function as calcineurin-interacting proteins that help tether calcineurin to the sarcomere of cardiac and skeletal muscle. They play an important role in modulation of calcineurin signaling. [provided by RefSeq, Apr 2012] This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 Myozenin 1 (MYOZ1) (NM_021245) Human Recombinant Protein – TP306448 Product images: Coomassie blue staining of purified MYOZ1 protein (Cat# TP306448).
    [Show full text]
  • Gene Expression and Genetic Variation in Human Atria
    NIH Public Access Author Manuscript Heart Rhythm. Author manuscript; available in PMC 2015 February 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Heart Rhythm. 2014 February ; 11(2): 266–271. doi:10.1016/j.hrthm.2013.10.051. Gene Expression and Genetic Variation in Human Atria Honghuang Lin, PhD, Elena V. Dolmatova, MD, Michael P. Morley, PhD, Kathryn L. Lunetta, PhD, David D. McManus, MD, ScM, Jared W. Magnani, MD, MSc, Kenneth B. Margulies, MD, Hakon Hakonarson, MD, PhD, Federica del Monte, MD, PhD, Emelia J. Benjamin, MD, ScM*, Thomas P. Cappola, MD, ScM*, and Patrick T. Ellinor, MD, PhD* National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study (H.L., K.L.L., D.D.M, J.W.M., E.J.B.), Framingham, MA, USA; Section of Computational Biomedicine (H.L.), Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Cardiology Division, Department of Medicine, and Epidemiology Division, Department of Quantitative Health Sciences (D.D.M.), University of Massachusetts Medical School, Worcester, MA, USA; Penn Cardiovascular Institute (M.P.M., T.P.C., K.B.M., H.H.), University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Department of Biostatistics (K.L.L.), Boston University School of Public Health, Boston, MA, USA; Section of Cardiovascular Medicine (J.W.M., E.J.B.), Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Section of Preventive Medicine (E.J.B.), Department of Medicine, Boston
    [Show full text]
  • MYOZ1 Antibody (Center) Blocking Peptide Synthetic Peptide Catalog # Bp5248c
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 MYOZ1 Antibody (Center) Blocking Peptide Synthetic peptide Catalog # BP5248c Specification MYOZ1 Antibody (Center) Blocking MYOZ1 Antibody (Center) Blocking Peptide - Peptide - Background Product Information Myozenins may serve as intracellular binding Primary Accession Q9NP98 proteins involved in linking Z-disk proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing MYOZ1 Antibody (Center) Blocking Peptide - Additional Information calcineurin signaling to the sarcomere. This protein plays an important role in the modulation of calcineurin signaling, may play a Gene ID 58529 role in myofibrillogenesis. Other Names MYOZ1 Antibody (Center) Blocking Myozenin-1, Calsarcin-2, Filamin-, actinin- Peptide - References and telethonin-binding protein, Protein FATZ, MYOZ1 (<a href="http://www.genena Aurino, S., et al. Acta Myol 27, 90-97 (2008) mes.org/cgi-bin/gene_symbol_report?hgnc_i Posch, M.G., et al. Mol. Genet. Metab. d=13752" target="_blank">HGNC:13752</a>) 91(2):207-208(2007)Arola, A.M., et al. Mol. Genet. Metab. 90(4):435-440(2007) Format Peptides are lyophilized in a solid powder format. Peptides can be reconstituted in solution using the appropriate buffer as needed. Storage Maintain refrigerated at 2-8°C for up to 6 months. For long term storage store at -20°C. Precautions This product is for research use only. Not for use in diagnostic or therapeutic procedures. MYOZ1 Antibody (Center) Blocking Peptide - Protein Information Name MYOZ1 (HGNC:13752) Function Myozenins may serve as intracellular binding proteins involved in linking Z-disk proteins such as alpha-actinin, gamma- filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere.
    [Show full text]
  • Discovery and Systematic Characterization of Risk Variants and Genes For
    medRxiv preprint doi: https://doi.org/10.1101/2021.05.24.21257377; this version posted June 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 1 Discovery and systematic characterization of risk variants and genes for 2 coronary artery disease in over a million participants 3 4 Krishna G Aragam1,2,3,4*, Tao Jiang5*, Anuj Goel6,7*, Stavroula Kanoni8*, Brooke N Wolford9*, 5 Elle M Weeks4, Minxian Wang3,4, George Hindy10, Wei Zhou4,11,12,9, Christopher Grace6,7, 6 Carolina Roselli3, Nicholas A Marston13, Frederick K Kamanu13, Ida Surakka14, Loreto Muñoz 7 Venegas15,16, Paul Sherliker17, Satoshi Koyama18, Kazuyoshi Ishigaki19, Bjørn O Åsvold20,21,22, 8 Michael R Brown23, Ben Brumpton20,21, Paul S de Vries23, Olga Giannakopoulou8, Panagiota 9 Giardoglou24, Daniel F Gudbjartsson25,26, Ulrich Güldener27, Syed M. Ijlal Haider15, Anna 10 Helgadottir25, Maysson Ibrahim28, Adnan Kastrati27,29, Thorsten Kessler27,29, Ling Li27, Lijiang 11 Ma30,31, Thomas Meitinger32,33,29, Sören Mucha15, Matthias Munz15, Federico Murgia28, Jonas B 12 Nielsen34,20, Markus M Nöthen35, Shichao Pang27, Tobias Reinberger15, Gudmar Thorleifsson25, 13 Moritz von Scheidt27,29, Jacob K Ulirsch4,11,36, EPIC-CVD Consortium, Biobank Japan, David O 14 Arnar25,37,38, Deepak S Atri39,3, Noël P Burtt4, Maria C Costanzo4, Jason Flannick40, Rajat M 15 Gupta39,3,4, Kaoru Ito18, Dong-Keun Jang4,
    [Show full text]
  • A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase.
    [Show full text]
  • Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling
    cells Article Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling Sebastian Segin 1,2, Michael Berlin 1,2, Christin Richter 1, Rebekka Medert 1,2, Veit Flockerzi 3, Paul Worley 4, Marc Freichel 1,2 and Juan E. Camacho Londoño 1,2,* 1 Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, INF 366, 69120 Heidelberg, Germany; [email protected] (S.S.); [email protected] (M.B.); [email protected] (C.R.); [email protected] (R.M.); [email protected] (M.F.) 2 DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany 3 Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany; [email protected] 4 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-54-86863; Fax: +49-6221-54-8644 Received: 26 March 2020; Accepted: 24 April 2020; Published: 28 April 2020 Abstract: Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo.
    [Show full text]
  • Study of Z-Disc-Associated Signaling Networks in Skeletal Muscle Cells by Functional and Global Phosphoproteomics
    PHDTHESIS Study of Z-disc-associated Signaling Networks in Skeletal Muscle Cells by Functional and Global Phosphoproteomics Inaugural-Dissertation zur Erlangung der Doktorwürde der Fakultät für Biologie der Albert-Ludwigs-Universität Freiburg im Breisgau vorgelegt von Lena Reimann geboren in Bielefeld Freiburg im Breisgau 01.08.2016 Angefertigt am Institut für Biologie II AG Biochemie und Funktionelle Proteomforschung zellulärer Systeme unter der Leitung von Prof. Dr. Bettina Warscheid Dekan der Fakultät für Biologie: Prof. Dr. Wolfgang Driever Promotionsvorsitzender: Prof. Dr. Stefan Rotter Betreuer der Arbeit: Prof. Dr. Bettina Warscheid Referent: Prof. Dr. Bettina Warscheid Koreferent:Prof. Dr. Jörn Dengjel Drittprüfer: Prof. Dr. Gerald Radziwill Datum der mündlichen Prüfung:21.10.2016 ART IS I, science is we. - Claude Bernard Zusammenfassung Als essentielle, strukturgebende Komponente des Sarkomers spielt die Z-Scheibe eine maßge- liche Rolle für die Funktionalität der quergestreiften Muskulatur. Die stetige Identifizierung von neuen Z-Scheiben-lokalisierten Proteinen, sowie deren Relevanz in muskulären Krankheits- bildern, hat die Z-Scheibe zunehmend in den Fokus der aktuellen Forschung gerückt. Neben ihrer strukturgebenden Funktion zeigen neuere Studien, dass die Z-Scheibe ein Hotspot für Signalprozesse in Muskelzellen ist. Bisher gibt es jedoch keine globalen Untersuchungen zur Aufklärung der komplexen Signalwege assoziiert mit dieser Struktur. Um Z-Scheiben-assoziierte Signalprozesse näher zu charakterisieren, wurde im ersten Teil dieser Arbeit eine großangelegte Phosphoproteomstudie mit ausdifferenzierten, kon- trahierenden C2C12 Myotuben durchgeführt. Zu diesem Zweck wurden die tryptisch ver- dauten Proteine mittels SCX-Chromatographie fraktioniert. Die anschließende Phosphopep- tidanreicherung erfolgte mit Titandioxid, gefolgt von einer hochauflösenden massenspek- trometrischen Analyse. Insgesamt wurden 11.369 Phosphorylierungsstellen, darunter 586 in sarkomerischen Proteinen gefunden.
    [Show full text]
  • Lack of Evidence for a Causal Role of CALR3 in Monogenic Cardiomyopathy
    European Journal of Human Genetics (2018) 26:1603–1610 https://doi.org/10.1038/s41431-018-0208-1 ARTICLE Lack of evidence for a causal role of CALR3 in monogenic cardiomyopathy 1 1 2 3 1 Judith M. A. Verhagen ● Job H. Veldman ● Paul A. van der Zwaag ● Jan H. von der Thüsen ● Erwin Brosens ● 4 5 6 4 Imke Christiaans ● Dennis Dooijes ● Apollonia T. J. M. Helderman-van den Enden ● Ronald H. Lekanne Deprez ● 7 8 1 5 Michelle Michels ● Anneke M. van Mil ● Rogier A. Oldenburg ● Jasper J. van der Smagt ● 6 1 1 1 Arthur van den Wijngaard ● Marja W. Wessels ● Robert M. W. Hofstra ● Marjon A. van Slegtenhorst ● 2 1 Jan D. H. Jongbloed ● Ingrid M. B. H. van de Laar Received: 12 January 2018 / Revised: 7 June 2018 / Accepted: 12 June 2018 / Published online: 9 July 2018 © The Author(s) 2018. This article is published with open access Abstract The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results are increasingly CALR3 1234567890();,: 1234567890();,: being used in medical decision making. In this study, we assessed the role of the calreticulin-3 gene ( )in cardiomyopathy. CALR3 has been included in several cardiomyopathy gene panels worldwide. Its inclusion is based on a single publication describing two missense variants in patients with hypertrophic cardiomyopathy. In our national cardiomyopathy cohort (n = 6154), we identified 17 unique, rare heterozygous CALR3 variants in 48 probands.
    [Show full text]