{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:48:41Z","timestamp":1789044521420,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Limb-Girdle Muscular Dystrophies (LGMDs) are genetically heterogeneous disorders primarily affecting proximal limb muscles. The most common form, LGMDR1, results from biallelic CAPN3 mutations encoding calpain-3, a muscle-specific protease. Recently, growing evidence implicates heterozygous CAPN3 variants in autosomal dominant disease (LGMDD4), with pathogenic mechanisms still incompletely understood. In a retrospective multicenter Italian study of patients harboring monoallelic CAPN3 variants (ClinicalTrials.gov NCT05956132), the p.Asp753Asn substitution was the most frequent change, detected in eight unrelated individuals. These patients, aged 6\u201380 years, exhibited a spectrum of presentations ranging from asymptomatic hyperCKemia and exertional myalgia to mild proximal weakness. Muscle biopsies showed mild, nonspecific myopathic changes, while calpain-3 expression was variably reduced. Structural modeling suggested that Asp753 may stabilize the Ca2+-bound conformation, with substitution potentially disrupting inter-domain interactions. Literature review identified 31 additional reports worldwide, confirming recurrence while highlighting marked phenotypic heterogeneity and limited clinical annotation. The aggregated evidence supports a pathogenic role for p.Asp753Asn, though the precise mechanism, potentially involving a dominant-negative effect, remains to be validated. These findings emphasize diagnostic challenges posed by single CAPN3 variants and underscore the need for integrated clinical, segregation, and functional studies to clarify pathogenic mechanisms, refine counseling, and guide patient-specific rehabilitation and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms262311384","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:46:18Z","timestamp":1764067578000},"page":"11384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recurrent CAPN3 p.Asp753Asn Variant Supports a Potential Dominant Calpainopathy with Variable Clinical Expressivity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3380-8706","authenticated-orcid":false,"given":"Giorgia","family":"D\u2019Este","sequence":"first","affiliation":[{"name":"Neurobiology Laboratory, San Camillo IRCCS, Via Alberoni 70, 30126 Venezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-6150","authenticated-orcid":false,"given":"Alejandro","family":"Giorgetti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Cassandrini","sequence":"additional","affiliation":[{"name":"UOC Immunologia, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37134 Verona, Italy"},{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Magri","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, IRCCS Fondazione Ca\u2019 Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 28, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6093-9816","authenticated-orcid":false,"given":"Dario","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS Fondazione Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dino Ferrari Center, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rubegni","sequence":"additional","affiliation":[{"name":"IRCCS Stella Maris Foundation, Viale del Tirreno 341, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-0482","authenticated-orcid":false,"given":"Diego","family":"Lopergolo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy"},{"name":"UOC Neurologia, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 16, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-0845","authenticated-orcid":false,"given":"Alessandro","family":"Malandrini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy"},{"name":"UOC Neurologia, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 16, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-1198","authenticated-orcid":false,"given":"Luciano","family":"Merlini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science (DIBINEM), University of Bologna, Piazza di Porta S. Donato 2, 40127 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3412-8339","authenticated-orcid":false,"given":"Gaetano","family":"Vattemi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Tonin","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7351-959X","authenticated-orcid":false,"given":"Rita","family":"Barresi","sequence":"additional","affiliation":[{"name":"Neurobiology Laboratory, San Camillo IRCCS, Via Alberoni 70, 30126 Venezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20106","DOI":"10.1016\/S0021-9258(19)47225-6","article-title":"Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types. Specific expression of the mRNA in skeletal muscle","volume":"264","author":"Sorimachi","year":"1989","journal-title":"J. Biol. 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