{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T23:56:30Z","timestamp":1787702190092,"version":"build-2784847793"},"reference-count":69,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"International Development Research"},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005155","name":"Azrieli Foundation","doi-asserted-by":"crossref","award":["3512\/19"],"award-info":[{"award-number":["3512\/19"]}],"id":[{"id":"10.13039\/501100005155","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023394","name":"Data Science Research Center, University of Haifa","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100023394","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005717","name":"University of Haifa","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005717","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Variants in the human receptor tyrosine kinase RET can cause RET loss-of-function and Hirschsprung's disease (HSCR), while activating RET variants drive cancers including multiple endocrine neoplasia type 2 (MEN2). Paradoxically, some variants cause both HSCR and MEN2A. We curated 77 RET extracellular positions associated with HSCR, MEN2A or both and used a structure-based approach to predict the effects of variants at these positions on RET structure. Approximately 90% of HSCR-associated positions can, upon mutation, disrupt intramolecular interactions stabilizing RET tertiary structure via distinct mechanisms. Only a minority perturb protein\u2212protein interactions needed for signal activation. In contrast, our analysis showed that \u223c75% of variants causing MEN2A lead to an unpaired cysteine that can form an intermolecular disulfide bond between two RET monomers. Other MEN2A variants are likely to enhance RET homodimerization via membrane-proximal extracellular interactions. Substitutions that, concurrently, destabilize RET structure and result in an unpaired cysteine are predicted to cause the paradoxical co-occurrence of HSCR and MEN2A. Our findings lay out a mechanistic basis for almost all identified pathological RET mutations, and suggest therapeutic strategies for targeting RET activity in HSCR and MEN2A.<\/jats:p>","DOI":"10.1242\/dmm.052748","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:03:06Z","timestamp":1773306186000},"source":"Crossref","is-referenced-by-count":2,"title":["Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions"],"prefix":"10.1242","volume":"19","author":[{"given":"Anna","family":"Fassler Bakhman","sequence":"first","affiliation":[{"name":"University of Haifa 1 Department of Human Biology, Faculty of Natural Science , , Haifa 3103301 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Cohen","sequence":"additional","affiliation":[{"name":"Ruth Rappaport Children's Hospital, Rambam Health Care Campus 2 Pediatric Endocrinology Unit , , Haifa 3109601 ,","place":["Israel"]},{"name":"Technion-Israel Institute of Technology 3 The Ruth & Bruce Rappaport Faculty of Medicine , , Haifa 3525433 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Kolodny","sequence":"additional","affiliation":[{"name":"University of Haifa 4 Department of Computer Science , , Haifa 3103301 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1807-4000","authenticated-orcid":false,"given":"Mickey","family":"Kosloff","sequence":"additional","affiliation":[{"name":"University of Haifa 1 Department of Human Biology, Faculty of Natural Science , , Haifa 3103301 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"2026042703035824100_DMM052748C1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026042703035824100_DMM052748C2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmg.2007.053959","article-title":"Hirschsprung disease, associated syndromes and genetics: a review","volume":"45","author":"Amiel","year":"2008","journal-title":"J. Med. Genet."},{"key":"2026042703035824100_DMM052748C3","doi-asserted-by":"publisher","first-page":"35808","DOI":"10.1074\/jbc.M104968200","article-title":"Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site","volume":"276","author":"Anders","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2026042703035824100_DMM052748C4","doi-asserted-by":"publisher","first-page":"2022-1-5","DOI":"10.7573\/dic.2022-1-5","article-title":"Non-small-cell lung cancer: how to manage RET-positive disease","volume":"11","author":"Andrini","year":"2022","journal-title":"Drugs Context."},{"key":"2026042703035824100_DMM052748C5","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1210\/me.2003-0173","article-title":"Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease","volume":"18","author":"Arighi","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"2026042703035824100_DMM052748C6","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1128\/MCB.15.3.1613","article-title":"Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations","volume":"15","author":"Asai","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"2026042703035824100_DMM052748C7","doi-asserted-by":"publisher","first-page":"e241","DOI":"10.1371\/journal.pcbi.0030241","article-title":"Stereochemical criteria for prediction of the effects of proline mutations on protein stability","volume":"3","author":"Bajaj","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"2026042703035824100_DMM052748C8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/prot.25638","article-title":"Residue-level determinants of angiopoietin-2 interactions with its receptor Tie2","volume":"87","author":"Bakhman","year":"2019","journal-title":"Proteins"},{"key":"2026042703035824100_DMM052748C9","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/S0896-6273(00)80649-2","article-title":"Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex","volume":"21","author":"Baloh","year":"1998","journal-title":"Neuron"},{"key":"2026042703035824100_DMM052748C10","doi-asserted-by":"publisher","first-page":"eaau4202","DOI":"10.1126\/sciadv.aau4202","article-title":"Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain","volume":"5","author":"Bigalke","year":"2019","journal-title":"Sci. Adv."},{"key":"2026042703035824100_DMM052748C11","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/S0039-6060(05)80057-1","article-title":"Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease","volume":"117","author":"Borst","year":"1995","journal-title":"Surgery"},{"key":"2026042703035824100_DMM052748C12","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1002\/j.1460-2075.1996.tb00632.x","article-title":"Molecular heterogeneity of RET loss of function in Hirschsprung's disease","volume":"15","author":"Carlomagno","year":"1996","journal-title":"EMBO J."},{"key":"2026042703035824100_DMM052748C13","doi-asserted-by":"publisher","first-page":"T105","DOI":"10.1530\/ERC-17-0303","article-title":"RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)","volume":"25","author":"Castellone","year":"2018","journal-title":"Endocr Relat. Cancer"},{"key":"2026042703035824100_DMM052748C14","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1111\/j.1365-2265.2009.03757.x","article-title":"A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization","volume":"73","author":"Castellone","year":"2010","journal-title":"Clin. Endocrinol."},{"key":"2026042703035824100_DMM052748C15","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1038\/sj.onc.1202202","article-title":"Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines","volume":"17","author":"Chappuis-Flament","year":"1998","journal-title":"Oncogene"},{"key":"2026042703035824100_DMM052748C16","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00467-013-2606-5","article-title":"To bud or not to bud: the RET perspective in CAKUT","volume":"29","author":"Davis","year":"2014","journal-title":"Pediatr. Nephrol."},{"key":"2026042703035824100_DMM052748C17","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0022-3468(98)90433-X","article-title":"Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene","volume":"33","author":"Decker","year":"1998","journal-title":"J. Pediatr. Surg."},{"key":"2026042703035824100_DMM052748C18","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1242\/dev.122.1.349","article-title":"Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts","volume":"122","author":"Durbec","year":"1996","journal-title":"Development"},{"key":"2026042703035824100_DMM052748C19","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/381789a0","article-title":"GDNF signalling through the Ret receptor tyrosine kinase","volume":"381","author":"Durbec","year":"1996","journal-title":"Nature"},{"key":"2026042703035824100_DMM052748C20","article-title":"Multiple endocrine neoplasia type 2","volume-title":"GeneReviews","author":"Eng","year":"1999"},{"key":"2026042703035824100_DMM052748C21","doi-asserted-by":"publisher","first-page":"103023","DOI":"10.1016\/j.sbi.2025.103023","article-title":"Leveraging protein structural information to improve variant effect prediction","volume":"92","author":"Gerasimavicius","year":"2025","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026042703035824100_DMM052748C22","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1016\/j.celrep.2014.08.040","article-title":"RET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association","volume":"8","author":"Goodman","year":"2014","journal-title":"Cell Rep."},{"key":"2026042703035824100_DMM052748C23","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/(SICI)1098-1004(200005)15:5&lt;418::AID-HUMU3&gt;3.0.CO;2-2","article-title":"RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems","volume":"15","author":"Hofstra","year":"2000","journal-title":"Hum. Mutat."},{"key":"2026042703035824100_DMM052748C24","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s12902-020-0544-3","article-title":"Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection","volume":"20","author":"Huang","year":"2020","journal-title":"BMC Endocr. Disord."},{"key":"2026042703035824100_DMM052748C25","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1093\/hmg\/5.10.1577","article-title":"Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain","volume":"5","author":"Iwashita","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"2026042703035824100_DMM052748C26","doi-asserted-by":"publisher","first-page":"8949","DOI":"10.1073\/pnas.0503259102","article-title":"Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence","volume":"102","author":"Kashuk","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026042703035824100_DMM052748C27","doi-asserted-by":"publisher","first-page":"514","DOI":"10.3803\/EnM.2021.1082","article-title":"Current Guidelines for Management of Medullary Thyroid Carcinoma","volume":"36","author":"Kim","year":"2021","journal-title":"Endocrinol. Metab."},{"key":"2026042703035824100_DMM052748C28","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1016\/j.jpedsurg.2006.03.051","article-title":"Novel mutations of RET gene in Korean patients with sporadic Hirschsprung's disease","volume":"41","author":"Kim","year":"2006","journal-title":"J. Pediatr. Surg."},{"key":"2026042703035824100_DMM052748C29","doi-asserted-by":"publisher","first-page":"7086","DOI":"10.1038\/sj.onc.1209698","article-title":"Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations","volume":"25","author":"Kjaer","year":"2006","journal-title":"Oncogene"},{"key":"2026042703035824100_DMM052748C30","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/384467a0","article-title":"Neurturin, a relative of glial-cell-line-derived neurotrophic factor","volume":"384","author":"Kotzbauer","year":"1996","journal-title":"Nature"},{"key":"2026042703035824100_DMM052748C31","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1002\/cncr.28661","article-title":"RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma","volume":"120","author":"Krampitz","year":"2014","journal-title":"Cancer"},{"key":"2026042703035824100_DMM052748C32","doi-asserted-by":"publisher","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2026042703035824100_DMM052748C33","doi-asserted-by":"publisher","first-page":"4277","DOI":"10.1021\/bi00613a026","article-title":"Conformational preferences of amino acids in globular proteins","volume":"17","author":"Levitt","year":"1978","journal-title":"Biochemistry"},{"key":"2026042703035824100_DMM052748C34","doi-asserted-by":"publisher","first-page":"e47650","DOI":"10.7554\/eLife.47650","article-title":"Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands","volume":"8","author":"Li","year":"2019","journal-title":"eLife"},{"key":"2026042703035824100_DMM052748C35","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.anpedi.2019.05.019","article-title":"New mutations associated with Hirschsprung disease","volume":"93","author":"Lorente-Ros","year":"2020","journal-title":"An. Pediatr. (Engl Ed)"},{"key":"2026042703035824100_DMM052748C36","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1530\/EC-18-0506","article-title":"Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study","volume":"8","author":"Maciel","year":"2019","journal-title":"Endocr. Connect."},{"key":"2026042703035824100_DMM052748C37","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/S0168-9525(01)02420-9","article-title":"The RET receptor: function in development and dysfunction in congenital malformation","volume":"17","author":"Manie","year":"2001","journal-title":"Trends Genet."},{"key":"2026042703035824100_DMM052748C38","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.semcancer.2021.03.035","article-title":"Multiple endocrine neoplasia type 2: a review","volume":"79","author":"Mathiesen","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"2026042703035824100_DMM052748C39","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/0022-2836(87)90038-6","article-title":"Interior and surface of monomeric proteins","volume":"196","author":"Miller","year":"1987","journal-title":"J. Mol. Biol."},{"key":"2026042703035824100_DMM052748C40","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1093\/hmg\/3.12.2163","article-title":"Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene","volume":"3","author":"Mulligan","year":"1994","journal-title":"Hum. Mol. Genet."},{"key":"2026042703035824100_DMM052748C41","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1002\/prot.340110407","article-title":"Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons","volume":"11","author":"Nicholls","year":"1991","journal-title":"Proteins"},{"key":"2026042703035824100_DMM052748C42","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1385\/EP:13:1:03","article-title":"RET\/PTC rearrangement in thyroid tumors","volume":"13","author":"Nikiforov","year":"2002","journal-title":"Endocr Pathol."},{"key":"2026042703035824100_DMM052748C43","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/sj.ejhg.5200971","article-title":"Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease","volume":"11","author":"Nishikawa","year":"2003","journal-title":"Eur. J. Hum. Genet."},{"key":"2026042703035824100_DMM052748C44","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1093\/oncolo\/oyac264","article-title":"RET fusion-positive non-small cell lung cancer: the evolving treatment landscape","volume":"28","author":"Novello","year":"2023","journal-title":"Oncologist"},{"key":"2026042703035824100_DMM052748C45","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/1471-2350-12-138","article-title":"Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events","volume":"12","author":"Nunez-Torres","year":"2011","journal-title":"BMC Med. Genet."},{"key":"2026042703035824100_DMM052748C46","doi-asserted-by":"publisher","first-page":"ENEURO.0534-20.2021","DOI":"10.1523\/ENEURO.0534-20.2021","article-title":"Increased RET activity coupled with a reduction in the RET gene dosage causes intestinal Aganglionosis in mice","volume":"8","author":"Okamoto","year":"2021","journal-title":"eNeuro"},{"key":"2026042703035824100_DMM052748C47","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1080\/07357900701518735","article-title":"The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland","volume":"25","author":"Paszko","year":"2007","journal-title":"Cancer Invest."},{"key":"2026042703035824100_DMM052748C48","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1172\/JCI375","article-title":"Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease","volume":"101","author":"Pelet","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2026042703035824100_DMM052748C49","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1002\/cncr.29044","article-title":"The RET oncogene in papillary thyroid carcinoma","volume":"121","author":"Prescott","year":"2015","journal-title":"Cancer"},{"key":"2026042703035824100_DMM052748C50","doi-asserted-by":"publisher","first-page":"932353","DOI":"10.3389\/fonc.2022.932353","article-title":"RET signaling pathway and RET inhibitors in human cancer","volume":"12","author":"Regua","year":"2022","journal-title":"Front. Oncol."},{"key":"2026042703035824100_DMM052748C51","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1126\/science.4023714","article-title":"Hydrophobicity of amino acid residues in globular proteins","volume":"229","author":"Rose","year":"1985","journal-title":"Science"},{"key":"2026042703035824100_DMM052748C52","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1097\/01.gim.0000245632.06064.f1","article-title":"A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes","volume":"8","author":"Ruiz-Ferrer","year":"2006","journal-title":"Genet. Med."},{"key":"2026042703035824100_DMM052748C53","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1002\/(SICI)1098-1004(200001)15:1&lt;122::AID-HUMU41&gt;3.0.CO;2-7","article-title":"A new germline mutation, R600Q, within the coding region of RET proto-oncogene: a rare polymorphism or a MEN 2 causing mutation?","volume":"15","author":"Saez","year":"2000","journal-title":"Hum. Mutat."},{"key":"2026042703035824100_DMM052748C54","doi-asserted-by":"publisher","first-page":"a009233","DOI":"10.1101\/cshperspect.a009233","article-title":"Central role of RET in thyroid cancer","volume":"5","author":"Santoro","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2026042703035824100_DMM052748C55","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1038\/367380a0","article-title":"Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret","volume":"367","author":"Schuchardt","year":"1994","journal-title":"Nature"},{"key":"2026042703035824100_DMM052748C56","doi-asserted-by":"publisher","first-page":"e28986","DOI":"10.1371\/journal.pone.0028986","article-title":"RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients","volume":"6","author":"So","year":"2011","journal-title":"PLoS ONE"},{"key":"2026042703035824100_DMM052748C57","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1542\/peds.109.5.914","article-title":"Hirschsprung's disease: a review","volume":"109","author":"Swenson","year":"2002","journal-title":"Pediatrics"},{"key":"2026042703035824100_DMM052748C58","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/S1359-6101(01)00012-0","article-title":"The GDNF\/RET signaling pathway and human diseases","volume":"12","author":"Takahashi","year":"2001","journal-title":"Cytokine Growth Factor. Rev."},{"key":"2026042703035824100_DMM052748C59","doi-asserted-by":"publisher","first-page":"112","DOI":"10.2183\/pjab.98.008","article-title":"RET receptor signaling: function in development, metabolic disease, and cancer","volume":"98","author":"Takahashi","year":"2022","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"2026042703035824100_DMM052748C60","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1002\/(SICI)1098-1004(1999)13:4&lt;331::AID-HUMU11&gt;3.0.CO;2-#","article-title":"Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?","volume":"13","author":"Takahashi","year":"1999","journal-title":"Hum. Mutat."},{"key":"2026042703035824100_DMM052748C61","doi-asserted-by":"publisher","first-page":"e80635","DOI":"10.1371\/journal.pone.0080635","article-title":"Maximum allowed solvent accessibilites of residues in proteins","volume":"8","author":"Tien","year":"2013","journal-title":"PLoS ONE"},{"key":"2026042703035824100_DMM052748C62","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1530\/ERC-13-0082","article-title":"Thyroid cancer and co-occurring RET mutations in Hirschsprung disease","volume":"20","author":"Virtanen","year":"2013","journal-title":"Endocr Relat. Cancer"},{"key":"2026042703035824100_DMM052748C63","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1002\/humu.22","article-title":"SNPs, protein structure, and disease","volume":"17","author":"Wang","year":"2001","journal-title":"Hum. Mutat."},{"key":"2026042703035824100_DMM052748C64","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1089\/thy.2014.0335","article-title":"Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma","volume":"25","author":"Wells","year":"2015","journal-title":"Thyroid"},{"key":"2026042703035824100_DMM052748C65","doi-asserted-by":"publisher","first-page":"7432","DOI":"10.1073\/pnas.102179699","article-title":"Evaluating conformational free energies: the colony energy and its application to the problem of loop prediction","volume":"99","author":"Xiang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026042703035824100_DMM052748C66","doi-asserted-by":"publisher","first-page":"7681","DOI":"10.1073\/pnas.0802896105","article-title":"Contacts between membrane proximal regions of the PDGF receptor ectodomain are required for receptor activation but not for receptor dimerization","volume":"105","author":"Yang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026042703035824100_DMM052748C67","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1073\/pnas.0914052107","article-title":"Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling","volume":"107","author":"Yang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026042703035824100_DMM052748C68","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1159\/000472371","article-title":"Heterogeneity and low detection rate of RET mutations in Hirschsprung disease","volume":"2","author":"Yin","year":"1994","journal-title":"Eur. J. Hum. Genet."},{"key":"2026042703035824100_DMM052748C69","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.cell.2007.05.055","article-title":"Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor","volume":"130","author":"Yuzawa","year":"2007","journal-title":"Cell"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052748\/3689779\/dmm052748.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052748\/3695983\/dmm052748.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052748\/3695983\/dmm052748.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T07:04:05Z","timestamp":1777273445000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/19\/4\/dmm052748\/371467\/Systematic-structure-based-analysis-of-RET"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":69,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.052748","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"article-number":"dmm052748"}}