Abstract

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

A significant proportion of individuals with inherited neuromuscular disease do not receive a genetic diagnosis. Here, the authors establish CCG expansions in the 5’ untranslated region of ABCD3 as a cause of oculopharyngodistal myopathy (OPDM) in individuals of European ancestry and identify increased expression of expansion-containing ABCD3 transcripts as a possible disease mechanism underlying muscle degeneration.

Details

Title
A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry
Author
Cortese, Andrea 1   VIAFID ORCID Logo  ; Beecroft, Sarah J. 2   VIAFID ORCID Logo  ; Facchini, Stefano 1 ; Curro, Riccardo 1 ; Cabrera-Serrano, Macarena 3   VIAFID ORCID Logo  ; Stevanovski, Igor 4   VIAFID ORCID Logo  ; Chintalaphani, Sanjog R. 4 ; Gamaarachchi, Hasindu 5 ; Weisburd, Ben 6   VIAFID ORCID Logo  ; Folland, Chiara 7 ; Monahan, Gavin 7   VIAFID ORCID Logo  ; Scriba, Carolin K. 8   VIAFID ORCID Logo  ; Dofash, Lein 7 ; Johari, Mridul 7 ; Grosz, Bianca R. 9   VIAFID ORCID Logo  ; Ellis, Melina 9 ; Fearnley, Liam G. 10   VIAFID ORCID Logo  ; Tankard, Rick 11   VIAFID ORCID Logo  ; Read, Justin 12 ; Merve, Ashirwad 13 ; Dominik, Natalia 14 ; Vegezzi, Elisa 15 ; Schnekenberg, Ricardo P. 1 ; Fernandez-Eulate, Gorka 16 ; Masingue, Marion 16 ; Giovannini, Diane 17 ; Delatycki, Martin B. 12 ; Storey, Elsdon 18 ; Gardner, Mac 19 ; Amor, David J. 12   VIAFID ORCID Logo  ; Nicholson, Garth 20   VIAFID ORCID Logo  ; Vucic, Steve 21   VIAFID ORCID Logo  ; Henderson, Robert D. 22 ; Robertson, Thomas 23 ; Dyke, Jason 24   VIAFID ORCID Logo  ; Fabian, Vicki 25 ; Mastaglia, Frank 26 ; Davis, Mark R. 27 ; Kennerson, Marina 28 ; Oflazer, Piraye 29 ; Başak, Nazli A. 29 ; Kayserili, Hülya 29 ; Yeşil, Gözde 30 ; Malfatti, Edoardo 31 ; Lilleker, James B. 32 ; Wicklund, Matthew 33 ; Pitceathly, Robert D. S. 14 ; Brady, Stefen 34 ; Brais, Bernard 35 ; Pellerin, David 36 ; Zuchner, Stephan 37 ; Danzi, Matt C. 37 ; Grandis, Marina 38 ; Comi, Giacomo P. 39 ; Corti, Stefania P. 40 ; Abati, Elena 39 ; Toscano, Antonio 41 ; Manini, Arianna 42 ; Ghia, Arianna 1 ; Tassorelli, Cristina 43 ; Quartesan, Ilaria 44 ; Simone, Roberto 14 ; Rossor, Alexander M. 14 ; Reilly, Mary M. 14 ; Carroll, Liam 45 ; Straub, Volker 46 ; Udd, Bjarne 47 ; Chen, Zhiyong 48 ; Bonne, Gisèle 49 ; Quinlivan, Ros 50 ; Hammans, Simon 45 ; Tucci, Arianna 51 ; Bahlo, Melanie 10   VIAFID ORCID Logo  ; McLean, Catriona A. 52   VIAFID ORCID Logo  ; Laing, Nigel G. 7 ; Stojkovic, Tanya 16 ; Houlden, Henry 14   VIAFID ORCID Logo  ; Hanna, Michael G. 14 ; Deveson, Ira W. 4   VIAFID ORCID Logo  ; Lockhart, Paul J. 12   VIAFID ORCID Logo  ; Lamont, Phillipa J. 53 ; Fahey, Michael C. 54   VIAFID ORCID Logo  ; Bugiardini, Enrico 14   VIAFID ORCID Logo  ; Ravenscroft, Gianina 7   VIAFID ORCID Logo 

1  UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); University of Pavia, Department of Brain and Behavioral Sciences, Pavia, Italy (GRID:grid.8982.b) (ISNI:0000 0004 1762 5736) 
2  Pawsey Supercomputing Research Centre, Kensington, Australia (GRID:grid.484570.a) 
3  Harry Perkins Institute of Medical Research, Nedlands, Australia (GRID:grid.431595.f) (ISNI:0000 0004 0469 0045); Hospital Universitario Virgen del Rocío/Universidad de Sevilla/CSIC, Department of Neurology and Instituto de Biomedicina de Sevilla, Sevilla, Spain (GRID:grid.414816.e) (ISNI:0000 0004 1773 7922) 
4  Garvan Institute of Medical Research, Genomics and Inherited Disease Program, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924); Garvan Institute of Medical Research and Murdoch Children’s Research Institute, Centre for Population Genomics, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924) 
5  Garvan Institute of Medical Research, Genomics and Inherited Disease Program, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924); Garvan Institute of Medical Research and Murdoch Children’s Research Institute, Centre for Population Genomics, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924); University of New South Wales, School of Computer Science and Engineering, Sydney, Australia (GRID:grid.1005.4) (ISNI:0000 0004 4902 0432) 
6  Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
7  Harry Perkins Institute of Medical Research, Nedlands, Australia (GRID:grid.431595.f) (ISNI:0000 0004 0469 0045); University of Western Australia, Centre for Medical Research, Nedlands, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
8  Harry Perkins Institute of Medical Research, Nedlands, Australia (GRID:grid.431595.f) (ISNI:0000 0004 0469 0045) 
9  ANZAC Research Institute, Northcott Neuroscience Laboratory, Sydney, Australia (GRID:grid.456991.6) (ISNI:0000 0004 0428 8494); University of Sydney, Faculty of Medicine and Health, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X) 
10  1 G Royal Parade, Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (GRID:grid.1042.7) (ISNI:0000 0004 0432 4889); 1G Royal Parade, Department of Medical Biology, The University of Melbourne, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
11  Curtin University, Department of Mathematics and Statistics, Perth, Australia (GRID:grid.1032.0) (ISNI:0000 0004 0375 4078) 
12  Murdoch Children’s Research Institute, Bruce Lefroy Centre, Parkville, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X); University of Melbourne, Royal Children’s Hospital, Department of Paediatrics, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
13  National Hospital for Neurology and Neurosurgery, Department of Neuropathology, London, United Kingdom (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631) 
14  UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631) 
15  IRCCS Mondino Foundation, Pavia, Italy (GRID:grid.419416.f) (ISNI:0000 0004 1760 3107) 
16  APHP, Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Hôpital Pitié-Salpêtrière, Institut de Myologie, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
17  Université Grenoble Alpes, CHU Grenoble Alpes, Grenoble Institut Neurosciences, INSERM, U1216, Grenoble, France (GRID:grid.450307.5) (ISNI:0000 0001 0944 2786) 
18  The Alfred Hospital, Neurology Department, Melbourne, Australia (GRID:grid.1623.6) (ISNI:0000 0004 0432 511X) 
19  University of Otago, The Laboratory for Genomic Medicine, Dunedin, New Zealand (GRID:grid.29980.3a) (ISNI:0000 0004 1936 7830) 
20  ANZAC Research Institute, Northcott Neuroscience Laboratory, Sydney, Australia (GRID:grid.456991.6) (ISNI:0000 0004 0428 8494); Concord Repatriation General Hospital, Molecular Medicine Laboratory, Sydney, Australia (GRID:grid.414685.a) (ISNI:0000 0004 0392 3935) 
21  University of Sydney, Faculty of Medicine and Health, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Concord Repatriation General Hospital, Brain and Nerve Research Centre, Sydney, Australia (GRID:grid.414685.a) (ISNI:0000 0004 0392 3935) 
22  Royal Brisbane & Women’s Hospital, Department of Neurology, Herston, Australia (GRID:grid.416100.2) (ISNI:0000 0001 0688 4634); UQ Centre for Clinical Research, Herston, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
23  Royal Brisbane and Women’s Hospital, Pathology Queensland, Herston, Australia (GRID:grid.416100.2) (ISNI:0000 0001 0688 4634); The University of Queensland, School of Biomedical Sciences, St. Lucia, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
24  Royal Perth Hospital, PathWest Neuropathology, Perth, Australia (GRID:grid.416195.e) (ISNI:0000 0004 0453 3875); University of Western Australia, School of Medicine and Pharmacology, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
25  Royal Perth Hospital, PathWest Neuropathology, Perth, Australia (GRID:grid.416195.e) (ISNI:0000 0004 0453 3875) 
26  Perron Institute for Neurological and Translational Science, Nedlands, Australia (GRID:grid.482226.8) (ISNI:0000 0004 0437 5686) 
27  PathWest, Neurogenetics Unit, Diagnostic Genomics, Nedlands, Australia (GRID:grid.2824.c) (ISNI:0000 0004 0589 6117) 
28  ANZAC Research Institute, Northcott Neuroscience Laboratory, Sydney, Australia (GRID:grid.456991.6) (ISNI:0000 0004 0428 8494); University of Sydney, Faculty of Medicine and Health, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Concord Repatriation General Hospital, Molecular Medicine Laboratory, Sydney, Australia (GRID:grid.414685.a) (ISNI:0000 0004 0392 3935) 
29  Department of Neurology, Koc University School of Medicine, Istanbul, Turkey (GRID:grid.15876.3d) (ISNI:0000 0001 0688 7552) 
30  Istanbul Medical Faculty, Department of Medical Genetics, Istanbul, Turkey (GRID:grid.9601.e) (ISNI:0000 0001 2166 6619) 
31  APHP, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Hôpital Henri Mondor, Créteil, France (GRID:grid.412116.1) (ISNI:0000 0004 1799 3934); IMRB, Université Paris Est, U955, INSERM, Créteil, France (GRID:grid.462410.5) (ISNI:0000 0004 0386 3258) 
32  Northern Care Alliance NHS Foundation Trust, Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Manchester, UK (GRID:grid.415721.4) (ISNI:0000 0000 8535 2371) 
33  UT Health San Antonio, San Antonio, USA (GRID:grid.516130.0) 
34  West Wing, Oxford Muscle Service, John Radcliffe Hospital, Level 3, Oxford, UK (GRID:grid.8348.7) (ISNI:0000 0001 2306 7492) 
35  McGill University, Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
36  UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); McGill University, Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
37  Miller School of Medicine, Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606) 
38  IRCCS Policlinico San Martino Hospital, Genoa, Italy (GRID:grid.410345.7) (ISNI:0000 0004 1756 7871); Università Di Genova, Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Genoa, Italy (GRID:grid.5606.5) (ISNI:0000 0001 2151 3065) 
39  University of Milan, Dino Ferrari Center, Department of Pathophysiology and Transplantation, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822); Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy (GRID:grid.414818.0) (ISNI:0000 0004 1757 8749) 
40  University of Milan, Dino Ferrari Center, Department of Pathophysiology and Transplantation, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822); Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit, Milan, Italy (GRID:grid.414818.0) (ISNI:0000 0004 1757 8749) 
41  University of Messina, ERN-NMD Center for Neuromuscular Disorders of Messina, Department of Clinical and Experimental Medicine, Messina, Italy (GRID:grid.10438.3e) (ISNI:0000 0001 2178 8421) 
42  University of Milan, Dino Ferrari Center, Department of Pathophysiology and Transplantation, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822) 
43  University of Pavia, Department of Brain and Behavioral Sciences, Pavia, Italy (GRID:grid.8982.b) (ISNI:0000 0004 1762 5736); IRCCS Mondino Foundation, Pavia, Italy (GRID:grid.419416.f) (ISNI:0000 0004 1760 3107) 
44  University of Pavia, Department of Brain and Behavioral Sciences, Pavia, Italy (GRID:grid.8982.b) (ISNI:0000 0004 1762 5736) 
45  University Hospital Southampton, Wessex Neurological Centre, Southampton, United Kingdom (GRID:grid.430506.4) 
46  John Walton Muscular Dystrophy Research Centre, Newcastle University Translational and Clinical Research Institute and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
47  Tampere Neuromuscular Center, Tampere, Finland (GRID:grid.1006.7); Folkhalsan Research Center, Helsinki, Finland (GRID:grid.428673.c) (ISNI:0000 0004 0409 6302) 
48  National Neuroscience Institute, Department of Neurology, Singapore, Singapore (GRID:grid.276809.2) (ISNI:0000 0004 0636 696X) 
49  Centre de Recherche en Myologie, Sorbonne Université, INSERM, Institut de Myologie, Paris, France (GRID:grid.418250.a) (ISNI:0000 0001 0308 8843) 
50  UCL Great Ormond Street Institute of Child Health & MRC Centre for Neuromuscular Diseases, Dubowitz Neuromuscular Centre, London, United Kingdom (GRID:grid.83440.3b) (ISNI:0000000121901201) 
51  UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); Queen Mary University of London, William Harvey Research Institute, Faculty of Medicine and Dentistry, London, United Kingdom (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
52  Parkville, Department of Medical Biology, The University of Melbourne, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Melbourne, Department of Anatomical Pathology, Alfred Hospital, Victoria, Australia (GRID:grid.1623.6) (ISNI:0000 0004 0432 511X) 
53  Royal Perth Hospital, Neurogenetics Unit, Perth, Australia (GRID:grid.416195.e) (ISNI:0000 0004 0453 3875) 
54  Department of Paediatrics Monash Children’s Hospital, Victoria, Australia (GRID:grid.460788.5) 
Pages
6327
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-49950-2
ProQuest document ID
3085153636
Copyright
© The Author(s) 2024. corrected publication 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.