{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:43:53Z","timestamp":1784673833429,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"},{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Ricerca Corrente 2024"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inclusion body myositis (IBM) is a slowly progressive disorder belonging to the idiopathic inflammatory myopathies, and it represents the most common adult-onset acquired myopathy. The main clinical features include proximal or distal muscular asymmetric weakness, with major involvement of long finger flexors and knee extensors. The main histological findings are the presence of fiber infiltrations, rimmed vacuoles, and amyloid inclusions. The etiopathogenesis is a challenge because both environmental and genetic factors are implicated in muscle degeneration and a distinction has been made previously between sporadic and hereditary forms. Here, we describe an Italian patient affected with a hereditary form of IBM with onset in his mid-forties. Next-generation sequencing analysis disclosed a heterozygous mutation c.76C&gt;T (p.Pro26Ser) in the PDZ motif of the LDB3\/ZASP gene, a mutation already described in a family with a late-onset myopathy and highly heterogenous degree of skeletal muscle weakness. In the proband\u2019s muscle biopsy, the expression of ZASP, myotilin, and desmin were increased. In our family, in addition to the earlier age of onset, the clinical picture is even more peculiar given the evidence, in one of the affected family members, of complete ophthalmoplegia in the vertical gaze. These findings help extend our knowledge of the clinical and genetic background associated with inclusion body myopathic disorders.<\/jats:p>","DOI":"10.3390\/ijms25126547","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T08:52:10Z","timestamp":1718355130000},"page":"6547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association between ZASP\/LDB3 Pro26Ser and Inclusion Body Myopathy"],"prefix":"10.3390","volume":"25","author":[{"given":"Daniela","family":"Piga","sequence":"first","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Zanotti","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9293-6823","authenticated-orcid":false,"given":"Michela","family":"Ripolone","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4607-8084","authenticated-orcid":false,"given":"Laura","family":"Napoli","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Ciscato","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-7288","authenticated-orcid":false,"given":"Sara","family":"Gibertini","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0932-5173","authenticated-orcid":false,"given":"Lorenzo","family":"Maggi","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7393-4205","authenticated-orcid":false,"given":"Andrea","family":"Rigamonti","sequence":"additional","affiliation":[{"name":"UOC Neurologia\u2013Stroke Unit, Presidio \u201cA. Manzoni\u201d, ASST Lecco, 23900 Lecco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-969X","authenticated-orcid":false,"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4593-4977","authenticated-orcid":false,"given":"Monica","family":"Sciacco","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3233\/JND-160198","article-title":"Systematic Review and Meta-Analysis of Prevalence Studies of Sporadic Inclusion Body Myositis","volume":"4","author":"Callan","year":"2017","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1007\/s00415-022-11459-3","article-title":"Inclusion body myositis: From genetics to clinical trials","volume":"270","author":"Nagy","year":"2023","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1055\/s-0032-1329197","article-title":"Inclusion body myositis","volume":"32","author":"Dimachkie","year":"2012","journal-title":"Semin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41584-019-0186-x","article-title":"Inclusion body myositis: Clinical features and pathogenesis","volume":"15","author":"Greenberg","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/1750-1172-9-88","article-title":"Sporadic inclusion body myositis: The genetic contributions to the pathogenesis","volume":"9","author":"Gang","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.bbadis.2014.08.007","article-title":"Hereditary inclusion-body myopathies","volume":"1852","author":"Broccolini","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.nmd.2024.03.001","article-title":"272nd ENMC international workshop: 10 Years of progress\u2014Revision of the ENMC 2013 diagnostic criteria for inclusion body myositis and clinical trial readiness. 16\u201318 June 2023, Hoofddorp, The Netherlands","volume":"37","author":"Lilleker","year":"2024","journal-title":"Neuromuscul. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26402","DOI":"10.1074\/jbc.M401871200","article-title":"The ZASP-like motif in actinin-associated LIM protein is required for interaction with the alpha-actinin rod and for targeting to the muscle Z-line","volume":"279","author":"Klaavuniemi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pathak, P., Blech-Hermoni, Y., Subedi, K., Mpamugo, J., Obeng-Nyarko, C., Ohman, R., Molloy, I., Kates, M., Hale, J., and Stauffer, S. (2021). Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKC\u03b1 and TSC2-mTOR downregulation. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-01864-1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1083\/jcb.146.2.465","article-title":"ZASP: A new Z-band alternatively spliced PDZ-motif protein","volume":"146","author":"Faulkner","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1023\/A:1023941703493","article-title":"PDZ domains-glue and guide","volume":"30","author":"Hendriks","year":"2003","journal-title":"Mol. Biol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13615","DOI":"10.1074\/jbc.M114.550418","article-title":"Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP) mutations in the actin-binding domain cause disruption of skeletal muscle actin filaments in myofibrillar myopathy","volume":"289","author":"Lin","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1016\/j.jacc.2003.10.021","article-title":"Mutations in Cypher\/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction","volume":"42","author":"Vatta","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.bbrc.2006.10.119","article-title":"Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy","volume":"351","author":"Theis","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1007\/s00415-012-6439-0","article-title":"Clinical, pathological, and genetic mutation analysis of sporadic inclusion body myositis in Japanese people","volume":"259","author":"Cai","year":"2012","journal-title":"J. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/ana.20376","article-title":"Mutations in ZASP define a novel form of muscular dystrophy in humans","volume":"57","author":"Selcen","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1093\/brain\/awm006","article-title":"Zaspopathy in a large classic late-onset distal myopathy family","volume":"130","author":"Griggs","year":"2007","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wadmore, K., Azad, A.J., and Gehmlich, K. (2021). The Role of Z-disc Proteins in Myopathy and Cardiomyopathy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063058"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.nmd.2020.11.008","article-title":"Protein aggregates and autophagy involvement in a family with a mutation in Z-band alternatively spliced PDZ-motif protein","volume":"31","author":"Cassandrini","year":"2021","journal-title":"Neuromuscul. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19807","DOI":"10.1074\/jbc.274.28.19807","article-title":"Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C","volume":"274","author":"Zhou","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40478-022-01354-3","article-title":"Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy","volume":"10","author":"Ripolone","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_22","unstructured":"Dubowitz, V., and Sewry, C.A. (2007). Muscle Biopsy, A Practical Approach, Saunders Elsevier. [3rd ed.]."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:58:25Z","timestamp":1760108305000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,14]]},"references-count":23,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25126547"],"URL":"https:\/\/doi.org\/10.3390\/ijms25126547","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,14]]}}}