{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:35:57Z","timestamp":1787117757929,"version":"build-2736575974"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Desmin is a muscle-specific intermediate filament protein crucial for maintaining cardiomyocyte structural integrity, connecting multiprotein complexes and organelles. Although\n                      <jats:italic toggle=\"yes\">DES<\/jats:italic>\n                      mutations are known to cause various (cardio)myopathies, many rare variants remain classified as variants of uncertain significance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We generated expression plasmids for 93 variants of uncertain significance located in the 1B domain and assessed filament formation in multiple cell lines, including cardiomyocytes derived from induced pluripotent stem cells. Filament assembly of purified wild-type and mutant desmin was analyzed using atomic force microscopy. Sequencing of 399 patients with severe dilated cardiomyopathy identified the DES-p.L187P variant in 1 individual. Desmin localization in explanted myocardial tissue from this patient was examined via immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Four variants (p.L159P, p.R163P, p.L187P, and p.E197del) caused filament formation defects, disrupting assembly even when coexpressed with wild-type desmin\u2014consistent with dominant inheritance. Atomic force microscopy revealed that these mutations impaired filament formation, resulting in small desmin complexes, while wild-type desmin formed regular filaments. Systematic proline substitutions across the 1B domain showed that insertions at hydrophobic a- and d-sites disrupted filament assembly, whereas others had minimal impact. Immunohistochemistry confirmed desmin disorganization in myocardial tissue from a\n                      <jats:italic toggle=\"yes\">DES<\/jats:italic>\n                      -p.L187P mutation carrier with dilated cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      The atlas of cardiomyopathy-associated desmin mutations represents a significant step toward improving the clinical interpretation of\n                      <jats:italic toggle=\"yes\">DES<\/jats:italic>\n                      variants associated with cardiomyopathies. Our data provide robust evidence that 4 variants of previously unknown significance listed in the ClinVar database warrant reclassification as likely pathogenic mutations based on their molecular effects. Specifically, we demonstrated that proline insertions\u2014particularly at positions where hydrophobic amino acids contribute to the intermolecular interactions between alpha helices\u2014lead to desmin filament assembly defects. These findings not only enhance our understanding of desmin-related cardiomyopathies but also offer a valuable resource for cardiologists and genetic counselors in guiding diagnosis, risk stratification, and patient counseling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005358","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:00:17Z","timestamp":1763114417000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Atlas of Cardiomyopathy Associated\n                    <i>DES<\/i>\n                    (Desmin) Mutations: Functional Insights Into the Critical 1B Domain"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6852-634X","authenticated-orcid":true,"given":"Sabrina","family":"Vo\u00df","sequence":"first","affiliation":[{"name":"Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW (S.V., H.M., M.S., S.H., J.R., J.G., A.B.), University Hospital of the Ruhr-University Bochum, Medical School OWL (University of Bielefeld), Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9722-0007","authenticated-orcid":true,"given":"Hendrik","family":"Milting","sequence":"additional","affiliation":[{"name":"Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW (S.V., H.M., M.S., S.H., J.R., J.G., A.B.), University Hospital of the Ruhr-University Bochum, Medical School OWL (University of Bielefeld), Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Klag","sequence":"additional","affiliation":[{"name":"Experimental Biophysics &amp; Applied Nanoscience, Faculty of Physics, Bielefeld University (F.K., J.R., M.G., D.A., 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Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5990-8368","authenticated-orcid":true,"given":"Jonas","family":"Reckmann","sequence":"additional","affiliation":[{"name":"Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW (S.V., H.M., M.S., S.H., J.R., J.G., A.B.), University Hospital of the Ruhr-University Bochum, Medical School OWL (University of Bielefeld), Germany."},{"name":"Experimental Biophysics &amp; Applied Nanoscience, Faculty of Physics, Bielefeld University (F.K., J.R., M.G., D.A., V.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3482-503X","authenticated-orcid":true,"given":"Manuel","family":"G\u00f6z","sequence":"additional","affiliation":[{"name":"Experimental Biophysics &amp; Applied Nanoscience, Faculty of Physics, Bielefeld University (F.K., J.R., M.G., D.A., 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