{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:38:20Z","timestamp":1792517900685,"version":"4.5.0"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T00:00:00Z","timestamp":1707004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"Common Fund","doi-asserted-by":"publisher","award":["U01HG010218"],"award-info":[{"award-number":["U01HG010218"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1HG008900"],"award-info":[{"award-number":["UM1HG008900"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000923","name":"Silicon Valley Community Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>ACTN2,<\/jats:italic> encoding alpha\u2010actinin\u20102, is essential for cardiac and skeletal muscle sarcomeric function. <jats:italic>ACTN2<\/jats:italic> variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2\u2010myopathy has also been proposed in a single series.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic <jats:italic>ACTN2<\/jats:italic> variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report seven patients from five families with a recurring biallelic variant in <jats:italic>ACTN2<\/jats:italic>: c.1516A&gt;G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder <jats:italic>ACTN2<\/jats:italic> variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an <jats:italic>in vitro<\/jats:italic> splicing assay, we show that c.1516A&gt;G <jats:italic>ACTN<\/jats:italic>2 does not impair normal splicing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This series further establishes <jats:italic>ACTN2<\/jats:italic> as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult\u2010onset progressive muscle disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51983","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T04:39:40Z","timestamp":1707107980000},"page":"629-640","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Recurring homozygous <scp>ACTN2<\/scp> variant (p.<scp>Arg506Gly<\/scp>) causes a recessive myopathy"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6399-1444","authenticated-orcid":false,"given":"Sandra","family":"Donkervoort","sequence":"first","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Mohassel","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"O'Leary","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon E.","family":"Bonner","sequence":"additional","affiliation":[{"name":"Stanford Center for Undiagnosed Diseases Stanford University  Stanford California USA"},{"name":"Department of Pediatrics, Medical Genetics Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taila","family":"Hartley","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute, University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Acquaye","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Brull","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahseen","family":"Mozaffar","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California  Irvine California USA"},{"name":"Department of Pathology &amp; Laboratory Medicine University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7142-9993","authenticated-orcid":false,"given":"Mario A.","family":"Saporta","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9085-3602","authenticated-orcid":false,"given":"David A.","family":"Dyment","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute, University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinda B.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Stanford Center for Undiagnosed Diseases Stanford University  Stanford California USA"},{"name":"Department of Neurology Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-0781","authenticated-orcid":false,"given":"Sander","family":"Pajusalu","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"},{"name":"Genetics and Personalized Medicine Clinic Tartu University Hospital  Tartu Estonia"},{"name":"Department of Clinical Genetics, Institute of Clinical Medicine University of Tartu  Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Austin\u2010Tse","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"},{"name":"Center for Genomic Medicine Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Hurth","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Developmental Medicine Hugo W. Moser Research Institute, Kennedy Krieger Institute  Baltimore Maryland USA"},{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"McWalter","sequence":"additional","affiliation":[{"name":"GeneDx  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi","family":"Warman\u2010Chardon","sequence":"additional","affiliation":[{"name":"Department of Medicine The Ottawa Hospital, University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Crunk","sequence":"additional","affiliation":[{"name":"GeneDx  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-1119","authenticated-orcid":false,"given":"A. Reghan","family":"Foley","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Mammen","sequence":"additional","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda Maryland USA"},{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Stanford Center for Undiagnosed Diseases Stanford University  Stanford California USA"},{"name":"Division of Cardiovascular Medicine Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"O'Donnell\u2010Luria","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"},{"name":"Center for Genomic Medicine Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Genetics and Genomics Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-2324","authenticated-orcid":false,"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-015-0029-7"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.12.001"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(03)00142-2"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.119"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000619"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25470"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-01963-8"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13697"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02363-7"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.231902.117"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lpm.2010.11.023"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27572"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-019-0186-x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26914"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22553"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(96)00361-6"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrcr.2019.10.001"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003419"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018789227987"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-194548"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24470"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51983","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T03:13:36Z","timestamp":1711422816000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,4]]},"references-count":22,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/acn3.51983"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51983","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,4]]},"assertion":[{"value":"2023-09-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}