{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:21:23Z","timestamp":1790230883183,"version":"4.1.0"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"6","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,6]]},"abstract":"<jats:sec><jats:title>Context<\/jats:title><jats:p>For rare and novel<jats:italic>RET<\/jats:italic>mutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify the<jats:italic>RET<\/jats:italic>mutation into one of the three clinical risk groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We analyzed proliferative properties and clinical implications associated with the<jats:italic>RET<\/jats:italic>protooncogene transmembrane domain mutation S649L.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>The transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>Fifteen individuals from five kindreds were identified as carriers of a<jats:italic>RET<\/jats:italic>protooncogene mutation in exon 11 codon 649 (TCG<jats:sup>Ser<\/jats:sup>\u2192TTG<jats:sup>Leu<\/jats:sup>). In two out of five index patients, a second<jats:italic>RET<\/jats:italic>mutation (C634W or V804L) was detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eight gene carriers were operated on. Histology revealed MTC and C-cell hyperplasia in three index and three screening patients respectively. In all other gene carriers (aged 41\u201364 years), calcitonin levels were in the normal range, and pentagastrin-stimulated calcitonin levels were &lt;100\u200apg\/ml. Therefore, thyroidectomy had not yet been performed. In one index patient carrying the S649L mutation, hyperparathyroidism was confirmed histologically.<jats:italic>RET<\/jats:italic>S649L-expressing NIH3T3 cells exhibited a clear increase of phosphotyrosine and proliferation rate when compared with parental NIH3T3 cells but a significantly lower kinase activity and cell growth rate when compared with<jats:italic>RET<\/jats:italic>C634R-expressing cells. When compared with<jats:italic>RET<\/jats:italic>C634R, the S649L mutant showed moderate transforming potential with small-sized colonies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our clinical and in vitro findings indicate that the transmembrane<jats:italic>RET<\/jats:italic>S649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-07-0817","type":"journal-article","created":{"date-parts":[[2008,4,11]],"date-time":"2008-04-11T15:58:49Z","timestamp":1207929529000},"page":"811-816","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":35,"title":["Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma."],"prefix":"10.1093","volume":"158","author":[{"given":"Mario","family":"Colombo-Benkmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenpeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"Riemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Hengst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Herbst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Keuser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Gro\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Rondot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedhelm","family":"Raue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Senninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte M","family":"P\u00fctzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Frank-Raue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"issue":"6428","key":"1_10248353","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/363458a0","volume":"363","author":"Mulligan","year":"1993","journal-title":"Nature; 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