{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:59:59Z","timestamp":1755799199244,"version":"3.44.0"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Dilated cardiomyopathy (DCM) is a heart muscle disease in which the left ventricle is enlarged, resulting in systolic dysfunction. Pathogenic variants in genes encoding proteins involved in cardiac contractility, cytoskeleton structure, and Ca\n              <jats:sup>2+<\/jats:sup>\n              handling have been associated with DCM.\n              <jats:italic toggle=\"yes\">TNNC1<\/jats:italic>\n              (cTnC [cardiac troponin C]) variants are implicated in DCM, hypertrophic, and restrictive cardiomyopathies. Unlike other sarcomere genes, most reports of\n              <jats:italic toggle=\"yes\">TNNC1<\/jats:italic>\n              variants lack segregation or pedigree data, partly because the majority of the variants described, to date, have been reported as de novo. Therefore, a critical need is warranted to further understand the mechanisms by which\n              <jats:italic toggle=\"yes\">TNNC1<\/jats:italic>\n              variants could impact myofilament function, especially in response to PKA (protein kinase A)\u2013mediated phosphorylation as this posttranslational modification modulates sarcomere function in response to \u03b2-adrenergic stimulation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Probands with the novel\n              <jats:italic toggle=\"yes\">TNNC1<\/jats:italic>\n              -c.404A&gt;C variant (cTnC-E135A) and family members were identified and consented. cTnC-depleted donor human cardiac muscle preparations were reconstituted with recombinant exogenous human cTnC-E135A. Steady-state isometric force and crossbridge kinetics were measured before and after PKA incubation. We used in silico modeling to further investigate crossbridge cycling kinetics.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We identified a multigenerational family carrying the\n              <jats:italic toggle=\"yes\">TNNC1<\/jats:italic>\n              -c.404A&gt;C variant with autosomal dominant DCM with both systolic and diastolic dysfunctions. Using reconstituted human cardiac muscle preparations, we showed that the cTnC-E135A abolishes the myofilament response to PKA-mediated phosphorylation. Furthermore, in silico mathematical modeling showed that this variant affects crossbridge kinetics by decreasing both Ca\n              <jats:sup>2+<\/jats:sup>\n              <jats:italic toggle=\"yes\">k<\/jats:italic>\n              <jats:sub>OFF<\/jats:sub>\n              -rate constant and myosin detachment rate, which could result in increased ventricular stiffness and reduced ejection fraction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Our clinical and genetics data, combined with the in silico modeling and functional assays, suggest that cTnC-E135A is associated with DCM and disrupts kinetics of Ca\n              <jats:sup>2+<\/jats:sup>\n              and crossbridge cycling by abolishing the myofilament response to PKA phosphorylation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.124.004720","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T09:00:09Z","timestamp":1752742809000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-8888","authenticated-orcid":true,"given":"Maicon","family":"Landim-Vieira","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine (M.L.-V., M.R.-G., R.C.C., J.H.L., S.P.C., J.R.P.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5120-0470","authenticated-orcid":true,"given":"Robin M.","family":"Perelli","sequence":"additional","affiliation":[{"name":"Florida State University, Tallahassee. Department of Cell Biology (R.M.P., A.P.L.), Duke University School of Medicine, Durham, NC."},{"name":"Division of Pediatric Cardiology, Department of Pediatrics (R.M.P., E.M., M.P.C., A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2407-1455","authenticated-orcid":true,"given":"Michelle","family":"Rodriguez-Garcia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine (M.L.-V., M.R.-G., R.C.C., J.H.L., S.P.C., J.R.P.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3811-4973","authenticated-orcid":true,"given":"Vivek P.","family":"Jani","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (V.P.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3571-2808","authenticated-orcid":true,"given":"Ronnie C.","family":"Chastain","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine (M.L.-V., M.R.-G., R.C.C., J.H.L., S.P.C., J.R.P.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3487-1014","authenticated-orcid":true,"given":"Joshua H.","family":"Lamar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine (M.L.-V., M.R.-G., R.C.C., J.H.L., S.P.C., J.R.P.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4403-5926","authenticated-orcid":true,"given":"Ellen","family":"Mines","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics (R.M.P., E.M., M.P.C., A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-4284","authenticated-orcid":true,"given":"Gwimoon","family":"Seo","sequence":"additional","affiliation":[{"name":"Protein Expression Facility, Institute of Molecular Biophysics (G.S.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9945-1909","authenticated-orcid":true,"given":"Aurelia","family":"Araujo Fernandes","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Federal University of Espirito Santo, Vit\u00f3ria, Brazil (A.A.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":true,"given":"Bjorn","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (B.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9875-7276","authenticated-orcid":true,"given":"Michael P.","family":"Carboni","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatrics (R.M.P., E.M., M.P.C., A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen P.","family":"Chelko","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine (M.L.-V., M.R.-G., R.C.C., J.H.L., S.P.C., J.R.P.), Duke University School of Medicine, Durham, NC."},{"name":"Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD (S.P.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-7565","authenticated-orcid":true,"given":"Vitold E.","family":"Galkin","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk (V.E.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9701-561X","authenticated-orcid":true,"given":"P. 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