{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:56:43Z","timestamp":1774033003204,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cMinisterium f\u00fcr Kultur und Wissenschaft des Landes Nordrhein\u2013Westfalen,\u201d"},{"name":"\u201cRegierenden B\u00fcrgermeister von Berlin\u2014Senatskanzlei Wissenschaft und Forschung,\u201d"},{"name":"\u201cBundesministerium f\u00fcr Bildung und Forschung\u201d"},{"name":"The European Regional Development Fund (ERDF)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>BICD2 variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in BICD2 were implicated in myopathies. Here, we present one patient with a known and six patients with novel BICD2 missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a BICD2-associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan. Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of BICD2-associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.<\/jats:p>","DOI":"10.3390\/ijms24076808","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T02:29:58Z","timestamp":1680748198000},"page":"6808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microscopic and Biochemical Hallmarks of BICD2-Associated Muscle Pathology toward the Evaluation of Novel Variants"],"prefix":"10.3390","volume":"24","author":[{"given":"Andreas","family":"Unger","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH), University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"Institute of Physiology II, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany"},{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"},{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-0092","authenticated-orcid":false,"given":"Andrea","family":"Gangfu\u00df","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0272-9220","authenticated-orcid":false,"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Leibniz-Institut f\u00fcr Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Gl\u00e4ser","sequence":"additional","affiliation":[{"name":"Genetikum, Center for Human Genetics, 89231 Neu-Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karsten","family":"Krause","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1465-6882","authenticated-orcid":false,"given":"Kristina","family":"Doering","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Hoffjan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1782-4642","authenticated-orcid":false,"given":"Matthias","family":"Vorgerd","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4017-940X","authenticated-orcid":false,"given":"Anne-Katrin","family":"G\u00fcttsches","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/ncb891","article-title":"Bicaudal-D regulates COPI-independent Golgi-ER transport by recruiting the dynein-dynactin motor complex","volume":"4","author":"Matanis","year":"2002","journal-title":"Nat. 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