{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T23:43:07Z","timestamp":1790120587939,"version":"4.0.1"},"reference-count":60,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-14-00059"],"award-info":[{"award-number":["22-14-00059"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pediatric dilated cardiomyopathy (DCM) is a rare heart muscle disorder leading to the enlargement of all chambers and systolic dysfunction. We identified a novel de novo variant, c.88A&gt;G (p.Lys30Glu, K30E), in the TPM1 gene encoding the major cardiac muscle tropomyosin (Tpm) isoform, Tpm1.1. The variant was found in a proband with DCM and left ventricular non-compaction who progressed to terminal heart failure at the age of 3 years and 8 months. To study the properties of the mutant protein, we produced recombinant K30E Tpm and used various biochemical and biophysical methods to compare its properties with those of WT Tpm. The K30E substitution decreased the thermal stability of Tpm and its complex with actin and significantly reduced the sliding velocity of the regulated thin filaments over a surface covered by ovine cardiac myosin in an in vitro motility assay across the entire physiological range of Ca2+ concentration. Our molecular dynamics simulations suggest that the charge reversal of the 30th residue of Tpm alters the actin monomer to which it is bound. We hypothesize that this rearrangement of the actin\u2013Tpm interaction may hinder the transition of a myosin head attached to a nearby actin from a weakly to a strongly bound, force-generating state, thereby reducing myocardial contractility. The impaired myosin interaction with regulated actin filaments and the decreased thermal stability of the actin\u2013Tpm complex at a near physiological temperature likely contribute to the pathogenicity of the variant and its causative role in progressive DCM.<\/jats:p>","DOI":"10.3390\/ijms252313059","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T04:13:03Z","timestamp":1733371983000},"page":"13059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-9546","authenticated-orcid":false,"given":"Elena V.","family":"Zaklyazminskaya","sequence":"first","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria V.","family":"Nefedova","sequence":"additional","affiliation":[{"name":"Research Center of Biotechnology, A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow 119071, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0238-4920","authenticated-orcid":false,"given":"Natalia A.","family":"Koubassova","sequence":"additional","affiliation":[{"name":"Institute of Mechanics, Lomonosov Moscow State University, Moscow 119192, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia P.","family":"Kotlukova","sequence":"additional","affiliation":[{"name":"Pediatrics Faculty of Medicine, Pirogov Russian National Research Medical University, Moscow 117997, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2976-2108","authenticated-orcid":false,"given":"Galina V.","family":"Kopylova","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620049, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5583-5342","authenticated-orcid":false,"given":"Anastasia M.","family":"Kochurova","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620049, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6660-4673","authenticated-orcid":false,"given":"Daniil V.","family":"Shchepkin","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620049, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia S.","family":"Ryabkova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russia"},{"name":"HyTest Ltd., 20520 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan A.","family":"Katrukha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russia"},{"name":"HyTest Ltd., 20520 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5085-0327","authenticated-orcid":false,"given":"Sergey Y.","family":"Kleymenov","sequence":"additional","affiliation":[{"name":"Research Center of Biotechnology, A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow 119071, Russia"},{"name":"Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5342-1739","authenticated-orcid":false,"given":"Sergey Y.","family":"Bershitsky","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620049, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Matyushenko","sequence":"additional","affiliation":[{"name":"Research Center of Biotechnology, A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow 119071, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-1525","authenticated-orcid":false,"given":"Andrey K.","family":"Tsaturyan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7755-9895","authenticated-orcid":false,"given":"Dmitrii I.","family":"Levitsky","sequence":"additional","affiliation":[{"name":"Research Center of Biotechnology, A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow 119071, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1053\/euhj.1998.1145","article-title":"Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy","volume":"20","author":"Mestroni","year":"1999","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Solaro, R.J., Goldspink, P.H., and Wolska, B.M. (2024). Emerging concepts of mechanisms controlling cardiac tension: Focus on familial dilated cardiomyopathy (DCM) and sarcomere-directed therapies. 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