{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:47:50Z","timestamp":1792813670860,"version":"4.5.0"},"reference-count":89,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"22","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,5,31]]},"abstract":"<jats:p>Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle \u03b3-actin (ACTG2) are the most common cause of the disease, but the mechanisms by which the mutations alter muscle function are unknown. Here, we examined four prevalent ACTG2 mutations (R40C, R148C, R178C, and R257C) that cause different disease severity and are spread throughout the actin fold. R178C displayed premature degradation, R148C disrupted interactions with actin-binding proteins, R40C inhibited polymerization, and R257C destabilized filaments. Because these mutations are heterozygous, we also analyzed 50\/50 mixtures with wild-type (WT) ACTG2. The WT\/R40C mixture impaired filament nucleation by leiomodin 1, and WT\/R257C produced filaments that were easily fragmented by smooth muscle myosin. Smooth muscle tropomyosin isoform Tpm1.4 partially rescued the defects of R40C and R257C. Cryo\u2013electron microscopy structures of filaments formed by R40C and R257C revealed disrupted intersubunit contacts. The biochemical and structural properties of the mutants correlate with their genotype-specific disease severity.<\/jats:p>","DOI":"10.1126\/sciadv.adn6615","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T17:58:33Z","timestamp":1717178313000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0364-1853","authenticated-orcid":true,"given":"Rachel H.","family":"Ceron","sequence":"first","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"The Children\u2019s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0312-870X","authenticated-orcid":true,"given":"Faviolla A.","family":"B\u00e1ez-Cruz","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1885-9019","authenticated-orcid":true,"given":"Nicholas J.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6120-5507","authenticated-orcid":true,"given":"Peter J.","family":"Carman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-023X","authenticated-orcid":true,"given":"Malgorzata","family":"Boczkowska","sequence":"additional","affiliation":[{"name":"Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3282-1765","authenticated-orcid":true,"given":"Robert O.","family":"Heuckeroth","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA."},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0544-9360","authenticated-orcid":true,"given":"E. 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R.","year":"2017","unstructured":"J. R. Whittington, A. T. Poole, E. H. Dutta, M. B. Munn, A novel mutation in ACTG2 gene in mother with chronic intestinal pseudoobstruction and fetus with megacystis microcolon intestinal hypoperistalsis syndrome. Case Rep. Genet. 2017, 9146507 (2017).","journal-title":"Case Rep. Genet."},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001204"},{"key":"e_1_3_2_88_2","first-page":"331","article-title":"ACTG2 associated visceral myopathy with intestinal pseudoobstruction","volume":"59","author":"Shen M. X.","year":"2021","unstructured":"M. X. Shen, C. Zhao, Y. J. Wang, X. W. Xin, Y. Yin, Y. P. Jin, ACTG2 associated visceral myopathy with intestinal pseudoobstruction. 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