{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:53:17Z","timestamp":1777423997130,"version":"3.51.4"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H03550"],"award-info":[{"award-number":["17H03550"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K19527"],"award-info":[{"award-number":["17K19527"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Dev Growth Differ"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Missense mutations of the <jats:italic>RET<\/jats:italic> gene have been identified in both multiple endocrine neoplasia (MEN) type 2A\/B and Hirschsprung disease (HSCR: congenital absence of the enteric nervous system, ENS). Current consensus holds that MEN2A\/B and HSCR are caused by activating and inactivating <jats:italic>RET<\/jats:italic> mutations, respectively. However, the biological significance of <jats:italic>RET<\/jats:italic> missense mutations in vivo has not been fully elucidated. In the present study, we introduced one MEN2B\u2010associated (M918T) and two HSCR\u2010associated (N394K and Y791F) <jats:italic>RET<\/jats:italic> missense mutations into the corresponding regions of the mouse <jats:italic>Ret<\/jats:italic> gene by genome editing (<jats:italic>Ret<jats:sup>M919T<\/jats:sup>, Ret<jats:sup>N396K<\/jats:sup><\/jats:italic> and <jats:italic>Ret<jats:sup>Y792F<\/jats:sup><\/jats:italic>) and performed histological examinations of <jats:italic>Ret<\/jats:italic>\u2010expressing tissues to understand the pathogenetic impact of each mutant in vivo. <jats:italic>Ret<jats:sup>M919T\/+<\/jats:sup><\/jats:italic> mice displayed MEN2B\u2010related phenotypes, including C\u2010cell hyperplasia and abnormal enlargement of the primary sympathetic ganglia. Similar sympathetic phenotype was observed in <jats:italic>Ret<jats:sup>M919T\/\u2010<\/jats:sup><\/jats:italic> mice, demonstrating a strong pathogenetic effect of the <jats:italic>Ret<\/jats:italic> M918T by a single\u2010allele expression. In contrast, no abnormality was found in the ENS of mice harboring the <jats:italic>Ret<\/jats:italic> N394K or Y791F mutation. Most surprisingly, single\u2010allele expression of <jats:italic>RET<\/jats:italic> N394K or Y791F was sufficient for normal ENS development, indicating that these <jats:italic>RET<\/jats:italic> mutants exert largely physiological function in vivo. This study reveals contrasting pathogenetic effects between MEN2B\u2010 and HSCR\u2010associated <jats:italic>RET<\/jats:italic> missense mutations, and suggests that some of HSCR\u2010associated <jats:italic>RET<\/jats:italic> missense mutations are by themselves neither inactivating nor pathogenetic and require involvement of other gene mutations for disease expressivity.<\/jats:p>","DOI":"10.1111\/dgd.12664","type":"journal-article","created":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T11:24:45Z","timestamp":1586517885000},"page":"214-222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B\u2010 and Hirschsprung disease\u2010associated missense mutations of the <i>RET<\/i> gene"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2118-8260","authenticated-orcid":false,"given":"Taichi","family":"Nakatani","sequence":"first","affiliation":[{"name":"Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan"},{"name":"Division of Pediatric Surgery Department of Surgery Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiro","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuhiro","family":"Yamamichi","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuta","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-1746","authenticated-orcid":false,"given":"Toshihiro","family":"Uesaka","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3619-8314","authenticated-orcid":false,"given":"Yuko","family":"Bitoh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery Department of Surgery Kobe 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