{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:02:23Z","timestamp":1788325343892,"version":"build-2803163510"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,3,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Pediatric\u2010onset restrictive cardiomyopathy (\n              <jats:styled-content style=\"fixed-case\">RCM<\/jats:styled-content>\n              ) is associated with high mortality, but underlying mechanisms of disease are under investigated.\n              <jats:styled-content style=\"fixed-case\">RCM<\/jats:styled-content>\n              \u2010associated diastolic dysfunction secondary to variants in\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n                2\n              <\/jats:italic>\n              \u2010encoded cardiac troponin T (\n              <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n              2) is poorly described.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Genetic analysis of a proband and kindred with\n              <jats:styled-content style=\"fixed-case\">RCM<\/jats:styled-content>\n              identified\n              <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n              2\u2010R94C, which cosegregated in a family with 2 generations of\n              <jats:styled-content style=\"fixed-case\">RCM<\/jats:styled-content>\n              , ventricular arrhythmias, and sudden death.\n              <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n              2\u2010R94C was absent among large, population\u2010based cohorts Genome Aggregation Database (gnomAD) and predicted to be pathologic by in silico modeling. Biophysical experiments using recombinant human\n              <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n              2\u2010R94C demonstrated impaired cardiac regulation at the molecular level attributed to reduced calcium\u2010dependent blocking of myosin's interaction with the thin filament. Computational modeling predicted a shift in the force\u2010calcium curve for the R94C mutant toward submaximal calcium activation compared within the wild type, suggesting low levels of muscle activation even at resting calcium concentrations and hypercontractility following activation by calcium.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The pathogenic\n              <jats:styled-content style=\"fixed-case\">TNNT<\/jats:styled-content>\n              2\u2010R94C variant activates thin\u2010filament\u2013mediated sarcomeric contraction at submaximal calcium concentrations, likely resulting in increased muscle tension during diastole and hypercontractility during systole. This describes the proximal biophysical mechanism for development of RCM in this family.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.015111","type":"journal-article","created":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T10:04:22Z","timestamp":1582711462000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Variant R94C in\n            <i>TNNT2<\/i>\n            \u2010Encoded Troponin T Predisposes to Pediatric Restrictive Cardiomyopathy and Sudden Death Through Impaired Thin Filament Relaxation Resulting in Myocardial Diastolic Dysfunction"],"prefix":"10.1161","volume":"9","author":[{"given":"Jordan E.","family":"Ezekian","sequence":"first","affiliation":[{"name":"Division of Paediatric Cardiology Department of Pediatrics Duke University School of Medicine Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah 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