{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T22:13:52Z","timestamp":1779142432396,"version":"3.51.4"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"vor","delay-in-days":41,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL107304"],"award-info":[{"award-number":["HL107304"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL081753"],"award-info":[{"award-number":["HL081753"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002822","name":"Central South University","doi-asserted-by":"crossref","award":["56021702"],"award-info":[{"award-number":["56021702"]}],"id":[{"id":"10.13039\/501100002822","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,8]]},"abstract":"<jats:p>\n                    Allelic heterogeneity (AH) has been noted in truncational\n                    <jats:italic>TTN<\/jats:italic>\n                    \u2013associated (\n                    <jats:italic>TTNtv<\/jats:italic>\n                    -associated) dilated cardiomyopathy (DCM); i.e., mutations affecting A-band\u2013encoding exons are pathogenic, but those affecting Z-disc\u2013encoding exons are likely benign. The lack of an in vivo animal model that recapitulates AH hinders the deciphering of the underlying mechanism. Here, we explored zebrafish as a candidate vertebrate model by phenotyping a collection of zebrafish\n                    <jats:italic>ttntv<\/jats:italic>\n                    alleles. We noted that cardiac function and sarcomere structure were more severely disrupted in\n                    <jats:italic>ttntv-A<\/jats:italic>\n                    than in\n                    <jats:italic>ttntv-Z<\/jats:italic>\n                    homozygous embryos. Consistently, cardiomyopathy-like phenotypes were present in\n                    <jats:italic>ttntv-A<\/jats:italic>\n                    but not\n                    <jats:italic>ttntv-Z<\/jats:italic>\n                    adult heterozygous mutants. The phenotypes observed in\n                    <jats:italic>ttntv-A<\/jats:italic>\n                    alleles were recapitulated in null mutants with the full\n                    <jats:italic>titin<\/jats:italic>\n                    -encoding sequences removed. Defective autophagic flux, largely due to impaired autophagosome-lysosome fusion, was also noted only in\n                    <jats:italic>ttntv-A<\/jats:italic>\n                    but not in\n                    <jats:italic>ttntv-Z<\/jats:italic>\n                    models. Moreover, we found that genetic manipulation of\n                    <jats:italic>ulk1a<\/jats:italic>\n                    restored autophagy flux and rescued cardiac dysfunction in\n                    <jats:italic>ttntv-A<\/jats:italic>\n                    animals. Together, our findings presented adult zebrafish as an in vivo animal model for studying AH in\n                    <jats:italic>TTNtv<\/jats:italic>\n                    DCM, demonstrated\n                    <jats:italic>TTN<\/jats:italic>\n                    loss of function is sufficient to trigger\n                    <jats:italic>ttntv<\/jats:italic>\n                    DCM in zebrafish, and uncovered\n                    <jats:italic>ulk1a<\/jats:italic>\n                    as a potential therapeutic target gene for\n                    <jats:italic>TTNtv<\/jats:italic>\n                    DCM.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.175501","type":"journal-article","created":{"date-parts":[[2024,4,7]],"date-time":"2024-04-07T14:00:31Z","timestamp":1712498431000},"source":"Crossref","is-referenced-by-count":7,"title":["Allelic heterogeneity of TTNtv dilated cardiomyopathy can be modeled in adult zebrafish"],"prefix":"10.1172","volume":"9","author":[{"given":"Ping","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiarong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA."},{"name":"Department of Cardiovascular Surgery, Second Xiangya Hospital, Central South University, Changsha, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feixiang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, 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