{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:38:24Z","timestamp":1791041904028,"version":"4.1.0"},"reference-count":65,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008732","name":"The Uehara Memorial Foundation","doi-asserted-by":"crossref","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"The Takeda Science Foundation","doi-asserted-by":"crossref","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["JP23H02872,JP20H03398,JP23K06230"],"award-info":[{"award-number":["JP23H02872,JP20H03398,JP23K06230"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP20ek0109470,JP23ek0109618"],"award-info":[{"award-number":["JP20ek0109470,JP23ek0109618"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,22]]},"abstract":"<jats:p>\n                    <jats:italic>Leucine-zipper\u2013like posttranslational regulator 1<\/jats:italic>\n                    (\n                    <jats:italic>LZTR1<\/jats:italic>\n                    ) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in\n                    <jats:italic>LZTR1<\/jats:italic>\n                    have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether\n                    <jats:italic>LZTR1<\/jats:italic>\n                    AD mutations regulate the proteostasis of the RAS subfamily molecules or cause NS-like phenotypes in vivo. To elucidate the pathogenesis of\n                    <jats:italic>LZTR1<\/jats:italic>\n                    mutations, we generated 2\n                    <jats:italic>LZTR1<\/jats:italic>\n                    mutation knock-in mice (\n                    <jats:italic>Lztr1<\/jats:italic>\n                    <jats:sup>G245R\/+<\/jats:sup>\n                    and\n                    <jats:italic>Lztr1<\/jats:italic>\n                    <jats:sup>R409C\/+<\/jats:sup>\n                    ), which correspond to the human p.G248R and p.R412C mutations, respectively. LZTR1-mutant male mice exhibit low birth weight, distinctive facial features, and cardiac hypertrophy. Cardiomyocyte size and the expression of RAS subfamily members, including MRAS and RIT1, were significantly increased in the left ventricles (LVs) of mutant male mice. LZTR1 AD mutants did not interact with RIT1 and functioned as dominant-negative forms of WT LZTR1. Multi-omics analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway was activated in the LVs of mutant mice. Treatment with the MEK inhibitor trametinib ameliorated cardiac hypertrophy in mutant male mice. These results suggest that the MEK\/ERK pathway is a therapeutic target for the NS-like phenotype resulting from dysfunction of RAS proteostasis by\n                    <jats:italic>LZTR1<\/jats:italic>\n                    AD mutations.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.182382","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T12:00:51Z","timestamp":1727784051000},"source":"Crossref","is-referenced-by-count":13,"title":["Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome\u2013like phenotypes in mice"],"prefix":"10.1172","volume":"9","author":[{"given":"Taiki","family":"Abe","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaho","family":"Morisaki","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Tohoku 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