DOCSLIB.ORG

Phenotypic Heterogeneity of Sarcomeric Gene Mutations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phenotypic Heterogeneity of Sarcomeric Gene Mutations View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 54, No. 4, 2009 © 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2009.04.029 Because titin was previously found to be associated with EDITORIAL COMMENT both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (6–8), CARP, as part of the titin complex, was also hypothesized to play a role in cardiomy- Phenotypic Heterogeneity of opathies. In this issue of the Journal, 2 reports (1,2) confirm this hypothesis and show that in fact ANKRD1 mutations Sarcomeric Gene Mutations can cause both DCM and HCM. Arimura et al. (2) report the results of the ANKRD1 A Matter of Gain and Loss?* mutation screening in a large HCM population collected in Japan and in the U.S. In 384 index patients, they found 3 Luisa Mestroni, MD missense mutations (ANKRD1 Pro52Ala, Thr123Met, and Ϸ Aurora, Colorado; and Trieste, Italy Ile280Val), accounting for 1% of HCM cases. Interest- ingly, they also investigated the N2A CARP-binding do- main of titin, and found 2 additional mutations (TTN Arg8500 and Arg8604Gln) in their HCM cohort. Moulik After several decades of intense research and various at- et al. (1) investigated a series of 208 DCM index patients of tempts at definition and classification, cardiomyopathies Japanese and U.S. origin, and found 3 missense mutations still remain disorders of remarkable and intriguing complex- (ANKRD1 Pro105Ser, which was recurrent in 2 families, ity. Once more, this aspect is elicited by the recent discovery Val107Leu, and Met1841Ile) accounting for 2% of DCM that mutations in the cardiac ankyrin repeat protein cases, further supporting a role of the titin mechanotrans- (CARP), a protein functionally part of the sarcomere, can duction complex in the pathogenesis of cardiomyopathies. cause different types of cardiomyopathies, as reported by But how to explain 2 different cardiomyopathies with Moulik et al. (1) and Arimura et al. (2) in this issue of the opposite pathophysiology caused by the same gene? Journal, as well as congenital heart disease (3). Phenotypic heterogeneity in cardiomyopathies. Pheno- typic heterogeneity (also called “allelic variants” in OMIM) See pages 325 and 334 (9) is a well-known and common phenomenon in genetics, referring to the occurrence of more than 1 phenotype caused ANKRD1 in normal heart and disease. CARP is a 36 kD by allelic mutations at a single locus (10); examples familiar protein encoded by the cardiac ankyrin repeat domain 1 to cardiologists are Duchenne and Becher muscular dystro- gene ANKRD1, which maps on chromosome 10. ANKRD1 phies caused by the same dystrophin gene, laminopathies is a member of a conserved gene family, coding for muscle ranging from progeria to lipodystrophy due to lamin A/C ankyrin repeat proteins (MARPs), involved in muscle stress gene, and LQT syndrome and congenital conduction defect response such as stretch, injury, and hypertrophy (4). CARP caused by the cardiac sodium channel gene SCN5A. is a nuclear transcription cofactor, a signaling molecule The reason for the clinical variability in allelic disorders predominantly expressed in the heart. CARP is found in the lies in the different function of the mutant proteins. In the sarcomere, where it colocalizes with the N2A domain of case of sarcomeric genes, it appears that a “gain” of function titin and myopalladin in the I-band of the Z disk (Fig. 1), usually results in increased energy demand, inefficient aden- and in the nucleus (4). The expression of CARP is con- osine triphosphate utilization, and hypertrophy, whereas a “loss” of function results in decreased contractility (Table 1). trolled, at least in part, by the titin-based mechanotrans- The 2 studies published in this issue seem to follow the rule. duction signaling pathway, and it is increased in heart Arimura et al. (2) show that ANKRD1 mutations in HCM development and conditions of injury and stress. In heart increase binding of CARP to titin and myopalladin, and development, CARP acts as a transcriptional repressor of that titin mutations at the CARP-binding site have the myocyte contractile elements. In heart failure, CARP is same effect. Conversely, Moulik et al. (1) show that overexpressed, suggesting a role in the “fetal gene program” ANKRD1 mutations in DCM cause a loss of CARP characteristic of the molecular remodeling of the failing binding to talin 1, potentially leading to loss of stretch- heart (5). sensing, disruption of the link between titin complex and cytoskeletal network, and transcriptional deregulation of genes involved in cell cycle and other pathways. *Editorials published in the Journal of the American College of Cardiology reflect the However, gain and loss are not the only mechanisms views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. involved in the phenotypic heterogeneity of ANKRD1. From the University of Colorado Cardiovascular Institute and Adult Medical Indeed, a recent publication by Cinquetti et al. (3) reports Genetics Program, University of Colorado at Denver and Health Sciences Center, the identification of increased CARP expression or pro- Aurora, Colorado; and Cluster in BioMedicine, Trieste, Italy. Supported by the National Institutes of Health (HL69071-01, MO1 RR00051-1575), American Heart tein stability in 3 cases with total anomalous pulmonary Association 0150453N, and Muscular Dystrophy Association PN0007-056. venous return, a rare congenital heart defect characterized 344 Mestroni JACC Vol. 54, No. 4, 2009 ANKRD1 and Heart Disease July 21, 2009:343–5 Figure 1 Model for the Titin-N2A Signaling Complex The sequence of N2A titin interacts with muscle ankyrin repeat proteins (MARPs) such as cardiac ankyrin repeat protein (CARP), ANKRD2, or diabetes-related ankyrin repeat protein. Myopalladin associates with the MARP/N2A complex by interacting with the N-terminal domains of MARPs. CAPN3 ϭ calpain 3; Ig ϭ immu- noglobulin; IS ϭ muscle specific sequence; NH2 ϭ N-terminal domain; PEVK ϭ sequence element rich in proline (P), glutamic acid (E), lysine (K), and valine (V) residues. Reprinted with permission from Miller et al. (4). by failure of the pulmonary veins to connect to the left Reprint requests and correspondence: Dr. Luisa Mestroni, atrium during development. In this case, CARP overex- Molecular Genetics, CUCVI, 12700 East 19th Avenue, Mail Stop pression or its increased activity are believed to repress F442, Aurora, Colorado 80045-6511. E-mail: Luisa.Mestroni@ normal cardiac gene expression, leading to abnormal ucdenver.edu. heart development. Impact of ANKRD1 mutations discovery in clinical REFERENCES care. The discovery of ANKRD1 mutations in cardiomy- opathies has several implications. First, it contributes to fill 1. Moulik M, Vatta M, Witt SH, et al. ANKRD1, the gene encoding the gap of the large number of patients in whom the cause cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. Ϸ J Am Coll Cardiol 2009;54:325–33. of cardiomyopathy is still unknown, 40% of cases in 2. Arimura T, Bos JM, Sato A, et al. Cardiac ankyrin repeat protein gene HCM and probably Ϸ70% in DCM (11). Second, it (ANKRD1) mutations in hypertrophic cardiomyopathy. J Am Coll expands our knowledge of the mechanisms leading to Cardiol 2009;54:334–42. 3. Cinquetti R, Badi I, Campione M, et al. Transcriptional deregulation hypertrophy and heart failure to include abnormal stretch- and a missense mutation define ANKRD1 as a candidate gene for total based signaling in response to force: this appears to be anomalous pulmonary venous return. Hum Mutat 2008;29:468–74. another “common pathway” for HCM and DCM that could 4. Miller MK, Bang ML, Witt CC, et al. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament- be targeted by novel therapeutic strategies. Finally, it raises based stress response molecules. J Mol Biol 2003;333:951–64. the question of clinical genetic testing of ANKRD1 in 5. Zolk O, Frohme M, Maurer A, et al. Cardiac ankyrin repeat protein, HCM and DCM patients. Although the low prevalence of a negative regulator of cardiac gene expression, is augmented in human heart failure. Biochem Biophys Res Commun 2002;293:1377–82. mutations may currently limit routine screening for the 6. Itoh-Satoh M, Hayashi T, Nishi H, et al. Titin mutations as the ANKRD1 gene, we may expect that the implementation of molecular basis of dilated cardiomyopathy. Biochem Biophys Res resequencing technology will allow a systematic screening Commun 2002;291:385–91. 7. Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding for rare cardiomyopathy genes in these patients in the near the giant muscle filament titin, cause familial dilated cardiomyopathy. future. Nature Genet 2002;30:201–4. JACC Vol. 54, No. 4, 2009 Mestroni 345 July 21, 2009:343–5 ANKRD1 and Heart Disease PhenotypicTable 1 HeterogeneityPhenotypic Heterogeneity of Sarcomeric of Genes Sarcomeric and Differential Genes and Changes Differential of Mutant Changes Protein of Mutant Function Protein Function Gene Protein DCM Function HCM Function Other Allelic Disorders Thick filament MYH7 Cardiac ␤ myosin heavy Yes 2Maximal force generation Yes 1Maximal force Laing distal myopathy, myosin chain 2Contractility generation storage myopathy, 2Velocity of actin sliding 1Caϩϩ sensitivity scapuloperoneal myopathy,
Load more

Recommended publications
  • S41598-018-33190-8.Pdf
    www.nature.com/scientificreports OPEN Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Received: 20 February 2018 Accepted: 25 September 2018 Osimertinib in EGFR-mutant Lung Published: xx xx xxxx Cancer Akiko Takahashi1, Masahiro Seike1, Mika Chiba1, Satoshi Takahashi1, Shinji Nakamichi1, Masaru Matsumoto1, Susumu Takeuchi1, Yuji Minegishi1, Rintaro Noro1, Shinobu Kunugi2, Kaoru Kubota1 & Akihiko Gemma1 Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial- mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR- TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs.
    [Show full text]
  • Comparative Transcriptome Analysis of Muscular Dystrophy Models Largemyd, Dmdmdx&Sol
    European Journal of Human Genetics (2016) 24, 1301–1309 & 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/16 www.nature.com/ejhg ARTICLE Comparative transcriptome analysis of muscular dystrophy models Largemyd, Dmdmdx/Largemyd and Dmdmdx: what makes them different? Camila F Almeida, Poliana CM Martins and Mariz Vainzof* Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of Mendelian diseases. The underlying pathophysiology and phenotypic variability in each form are much more complex, suggesting the involvement of many other genes. Thus, here we studied the whole genome expression profile in muscles from three mice models for MD, at different time points: Dmdmdx (mutation in dystrophin gene), Largemyd − / − (mutation in Large)andDmdmdx/Largemyd − / − (both mutations). The identification of altered biological functions can contribute to understand diseases and to find prognostic biomarkers and points for therapeutic intervention. We identified a substantial number of differentially expressed genes (DEGs) in each model, reflecting diseases' complexity. The main biological process affected in the three strains was immune system, accounting for the majority of enriched functional categories, followed by degeneration/regeneration and extracellular matrix remodeling processes. The most notable differences were in 21-day-old Dmdmdx, with a high proportion of DEGs related to its regenerative capacity. A higher number of positive embryonic myosin heavy chain (eMyHC) fibers confirmed this. The new Dmdmdx/Largemyd − / − model did not show a highly different transcriptome from the parental lineages, with a profile closer to Largemyd − / − , but not bearing the same regenerative potential as Dmdmdx.Thisisthefirst report about transcriptome profile of a mouse model for congenital MD and Dmdmdx/Largemyd.
    [Show full text]
  • Ankyrin Repeat Domain 1, ANKRD1, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer Lyndee L
    Cancer Therepy: Preclinical Ankyrin Repeat Domain 1, ANKRD1, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer Lyndee L. Scurr,1, 2 Alexander D. Guminski,1, 2 , 3 Yoke-Eng Chiew,1, 2 Rosemary L. Balleine,1, 5 Raghwa Sharma,4 Ying Lei,1, 2 Kylie Pryor,1, 2 Gerard V. Wain,2 Alison Brand,2 Karen Byth,6 Catherine Kennedy,1, 2 Helen Rizos,1Paul R. Harnett,1, 3 and Anna deFazio1, 2 Abstract Purpose:The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics. Experimental Design: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by associ- ation of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma. Results: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain1 (cardiac muscle). ANKRD1mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold.
    [Show full text]
  • The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Harvard University - DASH The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal Conditions and in Response to Pressure Overload The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Bang, Marie-Louise, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Citation Kenneth R. Chien, and Ju Chen. 2014. “The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal Conditions and in Response to Pressure Overload.” PLoS ONE 9 (4): e93638. doi:10.1371/journal.pone.0093638. http://dx.doi.org/10.1371/journal.pone.0093638. Published Version doi:10.1371/journal.pone.0093638 Accessed April 17, 2018 4:49:22 PM EDT Citable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12152896 This article was downloaded from Harvard University's DASH Terms of Use repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA (Article begins on next page) The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal Conditions and in Response to Pressure Overload Marie-Louise Bang1*, Yusu Gu2, Nancy D. Dalton2, Kirk L. Peterson2, Kenneth R. Chien3,4, Ju Chen2* 1 Institute of Genetic and Biomedical Research,
    [Show full text]
  • Histone Deacetylase Inhibitors for the Epigenetic Therapy of Proximal Spinal Muscular Atrophy
    Histone deacetylase inhibitors for the epigenetic therapy of proximal spinal muscular atrophy Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Universität zu Köln vorgelegt von Lutz Garbes aus Köln Köln 2010 The Doctoral Thesis "Histone deacetylase inhibitors for the epigenetic therapy of proximal spinal muscular atrophy“ was performed at the Institute of Human Genetics, Institute of Genetics and Centre for Molecular Medicine Cologne (CMMC) of the University of Cologne from November 2006 to 2010. Berichterstatter/in: Prof. Dr. rer. nat. Brunhilde Wirth Prof. Dr. rer. nat. Thomas Wiehe Tag der letzten mündlichen Prüfung: 22.11.2010 Für meine Eltern Acknowledgements First, I would like to thank my supervisor Brunhilde Wirth for giving me the opportunity to work on various interesting and challenging projects, for sharing her scientific knowledge and enthusiasm, and for allowing me to work independently. Furthermore, I woud like to thank her for motivating discussions and encouragement, for her generous support to attend scientific meetings, and for bringing me in touch with various scientist all over the world. I greatly appreciate her dedication. I thank my examiners Prof. Dr. Thomas Wiehe and Prof. Dr. Günter Schwarz. Of course a big “Thanks!” to all past and present members of the SMA group, and the whole Institute of Human Genetics in Cologne. A very big “extra thank you” to Irmgard Hölker for her excellent technical support during the last years, for countless triplicates and for staying at my side during the VPA odyssey. I thank the Markus Rießland for good advice whenever needed, valuable discussions about science, all the world and his wife and all the interesting news out there.
    [Show full text]
  • Autocrine IFN Signaling Inducing Profibrotic Fibroblast Responses By
    Downloaded from http://www.jimmunol.org/ by guest on September 23, 2021 Inducing is online at: average * The Journal of Immunology , 11 of which you can access for free at: 2013; 191:2956-2966; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication August 2013; doi: 10.4049/jimmunol.1300376 http://www.jimmunol.org/content/191/6/2956 A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Autocrine IFN Signaling Feng Fang, Kohtaro Ooka, Xiaoyong Sun, Ruchi Shah, Swati Bhattacharyya, Jun Wei and John Varga J Immunol cites 49 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130037 6.DC1 This article http://www.jimmunol.org/content/191/6/2956.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 23, 2021. The Journal of Immunology A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling Feng Fang,* Kohtaro Ooka,* Xiaoyong Sun,† Ruchi Shah,* Swati Bhattacharyya,* Jun Wei,* and John Varga* Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN.
    [Show full text]
  • Identification of the Genes Involved in Enhanced Fenretinide-Induced Apoptosis by Parthenolide in Human Hepatoma Cells
    Research Article Identification of the Genes Involved in Enhanced Fenretinide-Induced Apoptosis by Parthenolide in Human Hepatoma Cells Jeong-Hyang Park, Lan Liu, In-Hee Kim, Jong-Hyun Kim, Kyung-Ran You, and Dae-Ghon Kim Division of Gastroenterology and Hepatology, The Research Institute of Clinical Medicine, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk, Republic of Korea Abstract prostate cancer (6), bladder cancer (7), and a neuroblastoma (8) in Fenretinide (N-4-hydroxyphenyl retinamide, 4HPR) is a syn- preclinical experiments and in early clinical trials. It was previously thetic anticancer retinoid that is a well-known apoptosis- observed that fenretinide effectively induces apoptosis in hepato- ma cells (9, 10), and it was found that this ferentinide-induced inducing agent. Recently, we observed that the apoptosis n n induced by fenretinide could be effectively enhanced in apoptosis could be enhanced by the nuclear factor- B (NF- B) hepatoma cells by a concomitant treatment with parthenolide, inhibitor parthenolide. Fenretinide-induced cytotoxicity is retinoic which is a known inhibitor of nuclear factor-nnB (NF-nnB). acid receptor (RAR)–independent (11). However, fenretinide has Furthermore, treatment with fenretinide triggered the activa- been found to activate the RARs and several RAR-specific tion of NF-nnB during apoptosis, which could be substantially antagonists partially inhibited ferentinide-induced apoptosis (2). inhibited by parthenolide, suggesting that NF-nnB activation Therefore, both RAR-independent and RAR-dependent pathways are involved in the ferentinide-mediated apoptosis. Previously, it during fenretinide-induced apoptosis has an antiapoptotic effect. This study investigated the molecular mechanism of was observed that a lethal concentration of parthenolide could this apoptotic potentiation by NF-nnB inhibition.
    [Show full text]
  • The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal
    The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal Conditions and in Response to Pressure Overload Marie-Louise Bang1*, Yusu Gu2, Nancy D. Dalton2, Kirk L. Peterson2, Kenneth R. Chien3,4, Ju Chen2* 1 Institute of Genetic and Biomedical Research, UOS Milan, National Research Council and Humanitas Clinical and Research Center, Rozzano (Milan), Italy, 2 Department of Medicine, University of California San Diego, La Jolla, California, United States of America, 3 Department of Cell and Molecular Biology and Medicine, Karolinska Insititutet, Stockholm, Sweden, 4 Harvard University, Department of Stem Cell and Regenerative Biology, Cambridge, Massachusetts, United States of America Abstract Ankrd1/CARP, Ankrd2/Arpp, and Ankrd23/DARP belong to a family of stress inducible ankyrin repeat proteins expressed in striated muscle (MARPs). The MARPs are homologous in structure and localized in the nucleus where they negatively regulate gene expression as well as in the sarcomeric I-band, where they are thought to be involved in mechanosensing. Together with their strong induction during cardiac disease and the identification of causative Ankrd1 gene mutations in cardiomyopathy patients, this suggests their important roles in cardiac development, function, and disease. To determine the functional role of MARPs in vivo, we studied knockout (KO) mice of each of the three family members. Single KO mice were viable and had no apparent cardiac phenotype. We therefore hypothesized that the three highly homologous MARP proteins may have redundant functions in the heart and studied double and triple MARP KO mice. Unexpectedly, MARP triple KO mice were viable and had normal cardiac function both at basal levels and in response to mechanical pressure overload induced by transverse aortic constriction as assessed by echocardiography and hemodynamic studies.
    [Show full text]
  • New Gene for Dilated Cardiomyopathy
    RESEARCH HIGHLIGHTS NEW GENE FOR DILATED CARDIOMYOPATHY Three novel variants in the ankyrin repeat domain 1 (ANKRD1) gene, which encodes cardiac ankyrin repeat protein (CARP), have been identified in patients with dilated cardiomyopathy. Most of the ~20 genes that are known to be causative of dilated cardiomyopathy disrupt sarcomeric signalling pathways. “We selected ANKRD1 as a candidate due to its role in the Z-disk [in the sarcomere],” explains lead investigator Jeffrey Towbin. “Finding mutations, we developed a cellular model to define the mechanisms responsible.” Notably, CARP is upregulated in the cardiomyocytes of patients with hypertrophy and those with heart failure. The international team of researchers screened 160 patients from the UK and 80 patients from Japan. Heterozygous, missense sequence mutations in ANKRD1—resulting in P105S, V107L, and M184I mutations in CARP—were found in four (1.9%) of those tested, all of whom were male and from the UK. None of these mutations was found in a control sample of 180 healthy individuals. The patient with the V107L variant and one of the individuals with a P105S mutation had no family history of dilated cardiomyopathy. The carrier of the M184I variant had a sibling with left ventricular dilation, raising the possibility of autosomal-dominant inheritance. In yeast 2-hybrid assays, both the M184I and P105S variants were associated with a loss of CARP–Talin 1 binding, which could indicate disruption of stretch-signalling in the cardiomyocyte. Transfection of P105S and V107L variants into H9C2 rat embryonic myocardial cells led to altered regulation of several factors that contribute to apoptosis, cell- cycle control, and cell signalling.
    [Show full text]
  • Ankrd1, a Modulator of Matrix Metabolism and Cell-Matrix Interactions
    Ankrd1, a Modulator of Matrix Metabolism and Cell-Matrix Interactions By Karinna Almodóvar García Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University In partial fulfillment of the requirements For the degree of DOCTOR IN PHILOSOPHY in Cellular and Molecular Pathology August, 2014 Nashville, Tennessee Approved: David M. Bader, Ph.D. Jeffrey M. Davidson, Ph.D. Linda J. Sealy, Ph.D. Alissa M. Weaver, M.D., Ph.D Pampee P. Young, M.D., Ph.D. ABSTRACT Normal tissue repair involves a series of highly coordinated events that include inflammation, granulation tissue formation, revascularization, and tissue remodeling. The transcriptional co-factor, ankyrin repeat domain protein 1 (Ankrd1), is rapidly and highly up regulated by wounding and tissue injury in mouse skin. Ankrd1 is also strongly elevated in human wounds. Overexpression of Ankrd1 in wounds by adenoviral gene transfer enhances wound healing. Ankrd1 has dual roles: a transcriptional co-regulator of several genes and a structural component of the sarcomere, where it forms a multi- component complex with the giant elastic protein, titin. Deletion of Ankrd1 results in a wound healing phenotype characterized by impaired wound closure and reduced granulation tissue thickness. In vitro studies confirmed the importance of Ankrd1 for proper cell-matrix interaction. We identified two Ankrd1-target genes, Collagenase-3 (MMP-13) and Stromelysin-2 (MMP-10). Both, MMP-13 and MMP-10 are important players in matrix turnover during physiological and pathological events. In summary, Ankrd1 regulates genes involve in remodeling of the extracellular matrix and is essential for proper interaction with the extracellular matrix in vitro.
    [Show full text]
  • RNA-Sequencing Analysis Reveals New Alterations in Cardiomyocyte Cytoskeletal Genes in Patients with Heart Failure
    Laboratory Investigation (2014) 94, 645–653 & 2014 USCAP, Inc All rights reserved 0023-6837/14 RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure Isabel Herrer1, Esther Rosello´-Lletı´1, Miguel Rivera1, Marı´a Micaela Molina-Navarro1, Estefanı´a Tarazo´n1, Ana Ortega1, Luis Martı´nez-Dolz2, Juan Carlos Trivin˜o3, Francisca Lago4, Jose´ R Gonza´lez-Juanatey4, Vicente Bertomeu5, Jose´ Anastasio Montero6 and Manuel Portole´s1 Changes in cardiomyocyte cytoskeletal components, a crucial scaffold of cellular structure, have been found in heart failure (HF); however, the altered cytoskeletal network remains to be elucidated. This study investigated a new map of cytoskeleton-linked alterations that further explain the cardiomyocyte morphology and contraction disruption in HF. RNA-Sequencing (RNA-Seq) analysis was performed in 29 human LV tissue samples from ischemic cardiomyopathy (ICM; n ¼ 13) and dilated cardiomyopathy (DCM, n ¼ 10) patients undergoing cardiac transplantation and six healthy donors (control, CNT) and up to 16 ICM, 13 DCM and 7 CNT tissue samples for qRT-PCR. Gene Ontology analysis of RNA-Seq data demonstrated that cytoskeletal processes are altered in HF. We identified 60 differentially expressed cytoskeleton-related genes in ICM and 58 genes in DCM comparing with CNT, hierarchical clustering determined that shared cytoskeletal genes have a similar behavior in both pathologies. We further investigated MYLK4, RHOU, and ANKRD1 cytoskeletal components. qRT-PCR analysis revealed that MYLK4 was downregulated ( À 2.2-fold; Po0.05) and ANKRD1 was upregulated (2.3-fold; Po0.01) in ICM patients vs CNT. RHOU mRNA levels showed a statistical trend to decrease ( À 2.9-fold).
    [Show full text]
  • Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy
    Journal of the American College of Cardiology Vol. 54, No. 4, 2009 © 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2008.12.082 Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy Takuro Arimura, DVM, PHD,* J. Martijn Bos, MD,† Akinori Sato, MD,* Toru Kubo, MD, PHD,‡ Hiroshi Okamoto, MD, PHD,§ Hirofumi Nishi, MD, PHD,ʈ Haruhito Harada, MD, PHD,¶ Yoshinori Koga, MD, PHD,¶ Mousumi Moulik, MD,# Yoshinori L. Doi, MD, PHD,‡ Jeffrey A. Towbin, MD,** Michael J. Ackerman, MD, PHD,† Akinori Kimura, MD, PHD†† Tokyo, Kochi, Sapporo, Omuta, and Kurume, Japan; Rochester, Minnesota; Houston, Texas; and Cincinnati, Ohio Objectives The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. Background Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the car- diac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin. Methods We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations.
    [Show full text]