{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T10:44:46Z","timestamp":1769769886407,"version":"3.49.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,1,30]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Truncating variants in the\n                      <jats:italic toggle=\"yes\">TTN<\/jats:italic>\n                      gene (\n                      <jats:italic toggle=\"yes\">TTN<\/jats:italic>\n                      tv), encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We generated 6 zebrafish lines carrying truncating\n                      <jats:italic toggle=\"yes\">ttn.2<\/jats:italic>\n                      variants in the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts and protein levels was evaluated using quantitative polymerase chain reaction and proteomics. Phenotype analysis was performed during embryonic development and in adult hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Homozygous embryos from all lines except the C-terminal line, e232, showed a significant reduction of Z-disk and I-band\n                      <jats:italic toggle=\"yes\">ttn.2<\/jats:italic>\n                      transcripts, but A-band and M-band transcript levels were reduced only in lines with truncations distal to the\n                      <jats:italic toggle=\"yes\">cronos<\/jats:italic>\n                      promoter. These homozygous embryos uniformly died by 7 to 10 days postfertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to the\n                      <jats:italic toggle=\"yes\">cronos<\/jats:italic>\n                      promoter compared with those proximal. In contrast, homozygous e232 embryos, which lacked only the titin kinase and M-band regions, had relatively preserved cardiac function with incorporation of truncated Ttn.2\/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. All heterozygous embryos were phenotypically indistinguishable from wild type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our data suggest that cardiac and skeletal muscle dysfunction associated with truncating\n                      <jats:italic toggle=\"yes\">ttn.2<\/jats:italic>\n                      variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirements for C-terminal titin for maintenance of fast, slow, and cardiac muscle sarcomeres.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.325999","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T10:00:11Z","timestamp":1767780011000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (\n                    <i>ttn.2<\/i>\n                    ) Variants"],"prefix":"10.1161","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1549-3667","authenticated-orcid":true,"given":"Celine F.","family":"Santiago","sequence":"first","affiliation":[{"name":"Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research 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