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Primary Cilia Defects Causing Mitral Valve Prolapse Primary cilia defects causing mitral valve prolapse Toomer, K. A., Yu, M., Fulmer, D., Guo, L., Moore, K. S., Moore, R., Drayton, K. D., Glover, J., Peterson, N., Ramos-Ortiz, S., Drohan, A., Catching, B. J., Stairley, R., Wessels, A., Lipschutz, J. H., Delling, F. N., Jeunemaitre, X., Dina, C., Collins, R. L., ... Norris, R. A. (2019). Primary cilia defects causing mitral valve prolapse. Science Translational Medicine, 11(493), [eaax0290]. https://doi.org/10.1126/scitranslmed.aax0290 Published in: Science Translational Medicine Document Version: Peer reviewed version Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2019 AAAS. This work is made available online in accordance with the publisher’s policies. 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Oct. 2021 1 Primary cilia defects causing mitral valve prolapse 2 Katelynn Toomer1*, Mengyao Yu2,3*, Diana Fulmer1, Lilong Guo1, Kelsey Moore1, Reece Moore1, Ka’la Drayton1, 3 Janiece Glover1, Neal Peterson1, Sandra Ramos‐Ortiz1, Alex Drohan1, Breiona J. Catching1, Rebecca Stairley1, 4 Andy Wessels1, Joshua H. Lipschutz4,5, Francesca N. Delling6, Xavier Jeunemaitre2,3,7, Christian Dina8,9, Ryan L. 5 Collins10, Harrison Brand10, Michael E. Talkowski10, Federica del Monte11, Rupak Mukherjee11, Alexander 6 Awgulewitsch1, Simon Body12, Gary Hardiman13,14, Starr E. Hazard13, Willian Da Silveira13, Baolin Wang15, Maire 7 Leyne10, Ronen Durst16, Roger Markwald1, Solena Le Scouarnec8, Albert Hagege2,3,17, Thierry Le Tourneau8,9, 8 Peter Kohl18, Eva Rog‐Zielinska18, Patrick T. Ellinor19, Robert A. Levine20†, David Milan19,21†, Jean‐Jacques 9 Schott8,9†, Nabila Bouatia‐Naji2,3†, 10 Susan Slaugenhaupt10†, Russell A. Norris1†‡ 11 1Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, 12 College of Medicine, Children’s Research Institute, Medical University of South Carolina, 171 Ashley Avenue, 13 Charleston, SC 29425, USA. 14 2INSERM, UMR‐970, Paris Cardiovascular Research Center, 75015 Paris, France. 15 3Paris DescartesUniversity, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France. 16 4Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. 17 5Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA. 18 6Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 19 94143, USA. 20 7Assistance Publique–Hôpitaux de Paris, Département de Génétique, Hôpital Européen Georges Pompidou, 21 75015 Paris, France. 22 8INSERM, CNRS, Univ Nantes, L’Institut du Thorax, Nantes 44093, France. 23 9CHU Nantes, L’Institut du Thorax, Service de Cardiologie, Nantes 44093, France. 24 10Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, 25 Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA. 26 11Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of 27 South Carolina, Charleston, SC 29425, USA. 28 12Departmentof Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard 29 Medical School, Boston, MA 02115, USA. 30 13Center for Genomic Medicine,Medical University of South Carolina, 135 Cannon Street, Suite 303 MSC 835, 31 Charleston, SC 29425, USA. 32 14Faculty of Medicine, Health and Life Sciences School of Biological Sciences, Institute for Global Food Security 33 (IGFS), Queen’s University Belfast, Belfast, Northern Ireland, BT7 1NN, UK. 34 15Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA. 35 16Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem, Israel. 36 17Assistance Publique–Hôpitaux de Paris, Department of Cardiology, Hôpital Européen Georges Pompidou, 37 75015 Paris, France. 38 18University Heart Center Freiburg, Bad Krozingen and Faculty of Medicine of the Albert‐Ludwigs University 39 Freiburg, Institute for Experimental Cardiovascular Medicine, Elsässerstr 2Q, 79110 Freiburg, Germany. 40 19Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital Research Institute, 41 Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. 42 20 Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital Research Institute, 43 Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. 44 21Leducq Foundation, 265 Franklin Street, Suite 1902, Boston, MA, 02110, USA. 45 *These authors contributed equally to this work as first authors. 46 †These authors contributed equally to this work as senior authors. 47 ‡Corresponding author. Email: [email protected] 48 49 50 51 52 53 54 Abstract 55 Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. 56 MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease 57 are poorly understood. We now demonstrate that the defects in primary cilia genes and their regulated 58 pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and 59 genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac 60 development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and 61 profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal 62 dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1. A mouse model 63 harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during 64 development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary 65 cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with 66 MVP and controls from previously generated genome‐wide association studies (GWAS), which confirmed the 67 involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP 68 through altered cilia‐dependent regulation of ECM and suggest that defects in primary cilia genes can be 69 causative to disease phenotype in some patients with MVP 70 71 INTRODUCTION 72 Cilia are microtubule‐containing structures (axonemes) that project from the cell. There are two main types of 73 cilia: motile and immotile. Whereas motile cilia (>100 per cell) are largely used to move fluid or propel 74 gametes, immotile cilia (primary cilia) are solitary (typically one per cell), extending from the centriole/basal 75 body, and were previously thought to be vestigial evolutionary remnants with no persisting function (1). 76 However, this traditional belief was challenged by recent genetic discoveries that linked mutations in cilia 77 genes to a spectrum of rare syndromic diseases, now known as ciliopathies (2, 3). These findings spurred 78 concerted efforts to understand ciliogenesis and downstream pathways, as well as additional genetic 79 conditions that stem from defects in cilia structure and/or function. The emerging data suggest that primary 80 cilia are essential structures that function to transduce mechanical, electrical, and chemical signals in a tissue‐ 81 specific and time‐dependent context. In doing so, they relay growth factor [transforming growth factor– 82 (TGF) (4), platelet‐derived growth factor (PDGF) (5), WNT (6, 7), and Hedgehog (8)] and extracellular matrix 83 (ECM) (9) information from their surrounding microenvironment to influence cell survival, differentiation, and 84 tissue organization. Recent murine and human genetic discoveries have linked primary cilia to a spectrum of 85 disorders involving cardiac, renal, skeletal, and neurologic tissues (10–12). A classic example is the ciliopathy, 86 autosomal dominant polycystic kidney disease (ADPKD), in which ~25% of patients have mitral valve prolapse 87 (MVP), a 10‐fold increase above background (13, 14). Both MVP and ADPKD have a congenital etiology and are 88 characterized by excessive deposition of proteoglycans, as well as disorganization and fragmentation of the 89 collagen and elastin in the ECM (15, 16). These molecular changes, which culminate in abnormal tissue 90 hypertrophy, impair normal tissue architecture and function in both mitral valves and kidneys. The 91 comorbidity of MVP and ADPKD, in concert with the pathological similarities of disease phenotypes, raises the 92 possibility that MVP can be caused by cilia gene defects in some individuals. 93 94 RESULTS 95 Primary cilia are spatially and temporally regulated during 96 cardiac valve morphogenesis 97 Because clinical
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