{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:41:13Z","timestamp":1772160073121,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFA0801402, 2016YFC1000503, 2016YFC0905102"],"award-info":[{"award-number":["2019YFA0801402, 2016YFC1000503, 2016YFC0905102"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Limb\u2010girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a specific LGMD caused by a gene mutation encoding the calcium\u2010dependent neutral cysteine protease calpain\u20103 (CAPN3). In our study, the compound heterozygosity with two missense variants c.635\u2009T\u2009&gt;\u2009C (p.Leu212Pro) and c.2120A\u2009&gt;\u2009G (p.Asp707Gly) was identified in patients with LGMDR1. However, the pathogenicity of c.635\u2009T\u2009&gt;\u2009C has not been investigated. To evaluate the effects of this novel likely pathogenic variant to the motor system, the mouse model with c.635\u2009T\u2009&gt;\u2009C variant was prepared by CRISPR\/Cas9 gene editing technique. The pathological results revealed that a limited number of inflammatory cells infiltrated the endomyocytes of certain c.635\u2009T\u2009&gt;\u2009C homozygous mice at 10\u2009months of age. Compared with wild\u2010type mice, motor function was not significantly impaired in\n                    <jats:italic>Capn3<\/jats:italic>\n                    c. 635\u2009T\u2009&gt;\u2009C homozygous mice. Western blot and immunofluorescence assays further indicated that the expression levels of the Capn3 protein in muscle tissues of homozygous mice were similar to those of wild\u2010type mice. However, the arrangement and ultrastructural alterations of the mitochondria in the muscular tissues of homozygous mice were confirmed by electron microscopy. Subsequently, muscle regeneration of LGMDR1 was simulated using cardiotoxin (CTX) to induce muscle necrosis and regeneration to trigger the injury modification process. The repair of the homozygous mice was significantly worse than that of the control mice at day 15 and day 21 following treatment, the c.635\u2009T\u2009&gt;\u2009C variant of\n                    <jats:italic>Capn3<\/jats:italic>\n                    exhibited a significant effect on muscle regeneration of homozygous mice and induced mitochondrial damage. RNA\u2010sequencing results demonstrated that the expression levels of the mitochondrial\u2010related functional genes were significantly downregulated in the mutant mice. Taken together, the results of the present study strongly suggested that the LGMDR1 mouse model with a novel c.635\u2009T\u2009&gt;\u2009C variant in the\n                    <jats:italic>Capn3<\/jats:italic>\n                    gene was significantly dysfunctional in muscle injury repair via impairment of the mitochondrial function.\n                  <\/jats:p>","DOI":"10.1111\/cge.14330","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T06:10:45Z","timestamp":1680243045000},"page":"663-671","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Missense mutation of c.\n                    <scp>635\u2009T<\/scp>\n                    \u2009&gt;\u2009C in\n                    <scp>\n                      <i>CAPN3<\/i>\n                    <\/scp>\n                    impairs muscle injury repair in a\n                    <scp>Limb\u2010Girdel<\/scp>\n                    Muscular Dystropy Model"],"prefix":"10.1111","volume":"103","author":[{"given":"Hou\u2010Shi","family":"Ma","sequence":"first","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu\u2010Li","family":"Gong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology &amp; Shanghai Key Laboratory of Embryo and Reproduction Engineering  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Xiu","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Cai","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology &amp; Shanghai Key Laboratory of Embryo and Reproduction Engineering  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin\u2010Bing","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao\u2010Rui","family":"Ren","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology &amp; Shanghai Key Laboratory of Embryo and Reproduction Engineering  Shanghai 200040 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanyi","family":"Zeng","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, School of medicine Shanghai Jiao Tong University  Shanghai 200040 China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology &amp; Shanghai Key Laboratory of Embryo and Reproduction Engineering  Shanghai 200040 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