{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T14:09:25Z","timestamp":1789913365111,"version":"4.0.1"},"reference-count":55,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2018,1,16]],"date-time":"2018-01-16T00:00:00Z","timestamp":1516060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP16235"],"award-info":[{"award-number":["GGP16235"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DO 545\/8-1"],"award-info":[{"award-number":["DO 545\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2018,1,30]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic>p63<\/jats:italic>\n                    gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the\n                    <jats:italic>p63<\/jats:italic>\n                    gene can cause ankyloblepharon-ectodermal defects-cleft lip\/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63\u2019s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1713773115","type":"journal-article","created":{"date-parts":[[2018,1,16]],"date-time":"2018-01-16T11:39:02Z","timestamp":1516102742000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":53,"title":["Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome"],"prefix":"10.1073","volume":"115","author":[{"given":"Claudia","family":"Russo","sequence":"first","affiliation":[{"name":"Centro di Ingegneria Gentica e Biotecnologie Avanzate, 80145 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2144-583X","authenticated-orcid":false,"given":"Christian","family":"Osterburg","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sirico","sequence":"additional","affiliation":[{"name":"Centro di Ingegneria Gentica e Biotecnologie Avanzate, 80145 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Antonini","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy;"},{"name":"Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto di Ricerca Diagnostica e Nucleare (SDN), 80143 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto di Ricerca Diagnostica e Nucleare (SDN), 80143 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Maren","family":"W\u00fcrz","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Rinnenthal","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ferniani","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Kehrloesser","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"G\u00fcntert","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satrajit","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"D\u00f6tsch","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-5123","authenticated-orcid":false,"given":"Caterina","family":"Missero","sequence":"additional","affiliation":[{"name":"Centro di Ingegneria Gentica e Biotecnologie Avanzate, 80145 Naples, Italy;"},{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2018,1,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1101\/gad.1165104","article-title":"p63 is the molecular switch for initiation of an epithelial stratification program","volume":"18","author":"Koster MI","year":"2004","unstructured":"MI Koster, S Kim, AA Mills, FJ DeMayo, DR Roop, p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 18, 126\u2013131 (2004).","journal-title":"Genes Dev"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/19531","article-title":"p63 is a p53 homologue required for limb and epidermal morphogenesis","volume":"398","author":"Mills AA","year":"1999","unstructured":"AA Mills, , p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708\u2013713 (1999).","journal-title":"Nature"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1101\/gad.1406006","article-title":"Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation","volume":"20","author":"Nguyen BC","year":"2006","unstructured":"BC Nguyen, , Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20, 1028\u20131042 (2006).","journal-title":"Genes Dev"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.cell.2007.02.045","article-title":"p63 Is essential for the proliferative potential of stem cells in stratified epithelia","volume":"129","author":"Senoo M","year":"2007","unstructured":"M Senoo, F Pinto, CP Crum, F McKeon, p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129, 523\u2013536 (2007).","journal-title":"Cell"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1101\/gad.1463206","article-title":"p63 regulates proliferation and differentiation of developmentally mature keratinocytes","volume":"20","author":"Truong AB","year":"2006","unstructured":"AB Truong, M Kretz, TW Ridky, R Kimmel, PA Khavari, p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev 20, 3185\u20133197 (2006).","journal-title":"Genes Dev"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/19539","article-title":"p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development","volume":"398","author":"Yang A","year":"1999","unstructured":"A Yang, , p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714\u2013718 (1999).","journal-title":"Nature"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1038\/jid.2011.84","article-title":"p63, a story of mice and men","volume":"131","author":"Vanbokhoven H","year":"2011","unstructured":"H Vanbokhoven, G Melino, E Candi, W Declercq, p63, a story of mice and men. J Invest Dermatol 131, 1196\u20131207 (2011).","journal-title":"J Invest Dermatol"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S1097-2765(00)80275-0","article-title":"p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities","volume":"2","author":"Yang A","year":"1998","unstructured":"A Yang, , p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2, 305\u2013316 (1998).","journal-title":"Mol Cell"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.cell.2011.01.013","article-title":"DNA damage in oocytes induces a switch of the quality control factor TAp63\u03b1 from dimer to tetramer","volume":"144","author":"Deutsch GB","year":"2011","unstructured":"GB Deutsch, , DNA damage in oocytes induces a switch of the quality control factor TAp63\u03b1 from dimer to tetramer. Cell 144, 566\u2013576 (2011).","journal-title":"Cell"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/cdd.2009.139","article-title":"Conformational stability and activity of p73 require a second helix in the tetramerization domain","volume":"16","author":"Coutandin D","year":"2009","unstructured":"D Coutandin, , Conformational stability and activity of p73 require a second helix in the tetramerization domain. Cell Death Differ 16, 1582\u20131589 (2009).","journal-title":"Cell Death Differ"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ccr.2005.12.013","article-title":"p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis","volume":"9","author":"Rocco JW","year":"2006","unstructured":"JW Rocco, CO Leong, N Kuperwasser, MP DeYoung, LW Ellisen, p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9, 45\u201356 (2006).","journal-title":"Cancer Cell"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/nature05337","article-title":"p63 protects the female germ line during meiotic arrest","volume":"444","author":"Suh EK","year":"2006","unstructured":"EK Suh, , p63 protects the female germ line during meiotic arrest. 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Hum Mol Genet 22, 531\u2013543 (2013).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1002\/emmm.201100199","article-title":"Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome","volume":"4","author":"Ferone G","year":"2012","unstructured":"G Ferone, , Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. EMBO Mol Med 4, 192\u2013205 (2012).","journal-title":"EMBO Mol Med"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/jid.2009.438","article-title":"Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells","volume":"130","author":"Antonini D","year":"2010","unstructured":"D Antonini, , Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells. J Invest Dermatol 130, 1249\u20131257 (2010).","journal-title":"J Invest Dermatol"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"30574","DOI":"10.1074\/jbc.M109.049619","article-title":"p63 Suppresses non-epidermal lineage markers in a bone morphogenetic protein-dependent manner via repression of Smad7","volume":"284","author":"De Rosa L","year":"2009","unstructured":"L De Rosa, , p63 Suppresses non-epidermal lineage markers in a bone morphogenetic protein-dependent manner via repression of Smad7. J Biol Chem 284, 30574\u201330582 (2009).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.devcel.2010.10.015","article-title":"Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells","volume":"19","author":"LeBoeuf M","year":"2010","unstructured":"M LeBoeuf, , Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Dev Cell 19, 807\u2013818 (2010).","journal-title":"Dev Cell"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"4373","DOI":"10.1158\/0008-5472.CAN-11-0046","article-title":"Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma","volume":"71","author":"Ramsey MR","year":"2011","unstructured":"MR Ramsey, L He, N Forster, B Ory, LW Ellisen, Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. Cancer Res 71, 4373\u20134379 (2011).","journal-title":"Cancer Res"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1385\/CBB:44:3:475","article-title":"NMR structure of the p63 SAM domain and dynamical properties of G534V and T537P pathological mutants, identified in the AEC syndrome","volume":"44","author":"Cicero DO","year":"2006","unstructured":"DO Cicero, , NMR structure of the p63 SAM domain and dynamical properties of G534V and T537P pathological mutants, identified in the AEC syndrome. Cell Biochem Biophys 44, 475\u2013489 (2006).","journal-title":"Cell Biochem Biophys"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/hmg\/10.3.221","article-title":"Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63","volume":"10","author":"McGrath JA","year":"2001","unstructured":"JA McGrath, , Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10, 221\u2013229 (2001).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"4438","DOI":"10.1093\/emboj\/18.16.4438","article-title":"Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain","volume":"18","author":"Chi SW","year":"1999","unstructured":"SW Chi, A Ayed, CH Arrowsmith, Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain. EMBO J 18, 4438\u20134445 (1999).","journal-title":"EMBO J"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"e13909","DOI":"10.7554\/eLife.13909","article-title":"Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level","volume":"5","author":"Coutandin D","year":"2016","unstructured":"D Coutandin, , Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level. Elife 5, e13909 (2016).","journal-title":"Elife"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1038\/cddis.2009.1","article-title":"The C-terminus of p63 contains multiple regulatory elements with different functions","volume":"1","author":"Straub WE","year":"2010","unstructured":"WE Straub, , The C-terminus of p63 contains multiple regulatory elements with different functions. Cell Death Dis 1, e5 (2010).","journal-title":"Cell Death Dis"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1002\/ajmg.a.31271","article-title":"Pattern of p63 mutations and their phenotypes\u2013Update","volume":"140","author":"Rinne T","year":"2006","unstructured":"T Rinne, B Hamel, H van Bokhoven, HG Brunner, Pattern of p63 mutations and their phenotypes\u2013Update. 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Arch Dermatol 141, 1567\u20131573 (2005).","journal-title":"Arch Dermatol"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1111\/j.1742-4658.2011.08194.x","article-title":"Structural basis of p63\u03b1 SAM domain mutants involved in AEC syndrome","volume":"278","author":"Sathyamurthy A","year":"2011","unstructured":"A Sathyamurthy, SM Freund, CM Johnson, MD Allen, M Bycroft, Structural basis of p63\u03b1 SAM domain mutants involved in AEC syndrome. FEBS J 278, 2680\u20132688 (2011).","journal-title":"FEBS J"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1038\/nbt1012","article-title":"Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins","volume":"22","author":"Fernandez-Escamilla AM","year":"2004","unstructured":"AM Fernandez-Escamilla, F Rousseau, J Schymkowitz, L Serrano, Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. 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Cell Death Differ 23, 1952\u20131960 (2016).","journal-title":"Cell Death Differ"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nchembio.546","article-title":"Gain of function of mutant p53 by coaggregation with multiple tumor suppressors","volume":"7","author":"Xu J","year":"2011","unstructured":"J Xu, , Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 7, 285\u2013295 (2011).","journal-title":"Nat Chem Biol"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"11999","DOI":"10.1073\/pnas.0703458104","article-title":"DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2","volume":"104","author":"Candi E","year":"2007","unstructured":"E Candi, , DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci USA 104, 11999\u201312004 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/sj.jid.5700652","article-title":"A functional enhancer of keratin14 is a direct transcriptional target of deltaNp63","volume":"127","author":"Romano RA","year":"2007","unstructured":"RA Romano, B Birkaya, S Sinha, A functional enhancer of keratin14 is a direct transcriptional target of deltaNp63. J Invest Dermatol 127, 1175\u20131186 (2007).","journal-title":"J Invest Dermatol"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1242\/jcs.079327","article-title":"Differential altered stability and transcriptional activity of \u0394Np63 mutants in distinct ectodermal dysplasias","volume":"124","author":"Browne G","year":"2011","unstructured":"G Browne, , Differential altered stability and transcriptional activity of \u0394Np63 mutants in distinct ectodermal dysplasias. 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