A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry

• Published in: Nature communications Vol. 15; no. 1; pp. 6327 - 15
• Main Authors: Cortese, Andrea, Beecroft, Sarah J., Facchini, Stefano, Curro, Riccardo, Cabrera-Serrano, Macarena, Stevanovski, Igor, Chintalaphani, Sanjog R., Gamaarachchi, Hasindu, Weisburd, Ben, Folland, Chiara, Monahan, Gavin, Scriba, Carolin K., Dofash, Lein, Johari, Mridul, Grosz, Bianca R., Ellis, Melina, Fearnley, Liam G., Tankard, Rick, Read, Justin, Merve, Ashirwad, Dominik, Natalia, Vegezzi, Elisa, Schnekenberg, Ricardo P., Fernandez-Eulate, Gorka, Masingue, Marion, Giovannini, Diane, Delatycki, Martin B., Storey, Elsdon, Gardner, Mac, Amor, David J., Nicholson, Garth, Vucic, Steve, Henderson, Robert D., Robertson, Thomas, Dyke, Jason, Fabian, Vicki, Mastaglia, Frank, Davis, Mark R., Kennerson, Marina, Quinlivan, Ros, Hammans, Simon, Tucci, Arianna, Bahlo, Melanie, McLean, Catriona A., Laing, Nigel G., Stojkovic, Tanya, Houlden, Henry, Hanna, Michael G., Deveson, Ira W., Lockhart, Paul J., Lamont, Phillipa J., Fahey, Michael C., Bugiardini, Enrico, Ravenscroft, Gianina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 38; 45/23; 45/91; 5' Untranslated Regions; 631/208/1516; 692/617/375/374; Adolescent; Adult; Aged; ATP-Binding Cassette Transporters - genetics; Biopsy; Degeneration; Dysphagia; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Genetic screening; Humanities and Social Sciences; Humans; Inclusion bodies; Inclusions; Male; Middle Aged; multidisciplinary; Multiplexing; Muscle Weakness - genetics; Muscle Weakness - pathology; Muscle, Skeletal - pathology; Muscles; Muscular Dystrophies; Musculoskeletal system; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - pathology; Myopathy; Neuromuscular diseases; Overexpression; Pedigree; Population studies; Science; Science (multidisciplinary); Skeletal muscle; Trinucleotide Repeat Expansion - genetics; Vacuoles; White People - genetics; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49950-2

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.