{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:16:34Z","timestamp":1781072194696,"version":"3.54.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"17","funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200328 13"],"award-info":[{"award-number":["HG200328 13"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200388 05"],"award-info":[{"award-number":["HG200388 05"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G\u2009&gt;\u2009A p.(E17K) in AKT1. The presentation in affected individuals is variable, with a diversity of tissues demonstrating abnormalities. Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. We used two methods to create mouse models that had endogenously-regulated mosaic expression of the Proteus syndrome variant. Variant allele fractions (VAFs) ranged from 0% to 50% across numerous tissues in 44 Proteus syndrome mice. Mice were phenotypically heterogeneous with lesions rarely observed before 12\u00a0months of age. VMs were the most frequent finding with a total of 69 found in 29 of 44 Proteus syndrome mice. Twenty-eight cysts and ectasia, frequently biliary, were seen in 22 of 44 Proteus syndrome mice. Varying levels of mammary hyperplasia were seen in 10 of 16 female Proteus syndrome mice with other localized regions of hyperplasia and stromal expansion noted in several additional animals. Interestingly, 27 of 31 Proteus syndrome animals had non-zero blood VAF that is in contrast to the human disorder where it is rarely seen in peripheral blood. Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP\/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells. However, hyperplastic mammary epithelium was a mixture of GFP\/Akt1E17K-positive and negative cells with some GFP\/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner.<\/jats:p>","DOI":"10.1093\/hmg\/ddz116","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T15:12:40Z","timestamp":1559747560000},"page":"2920-2936","source":"Crossref","is-referenced-by-count":16,"title":["A mouse model of Proteus syndrome"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8816-9879","authenticated-orcid":false,"given":"Marjorie J","family":"Lindhurst","sequence":"first","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren R","family":"Brinster","sequence":"additional","affiliation":[{"name":"Division of Veterinary Resources, Office of Research Services, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C","family":"Kondolf","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine J","family":"Shwetar","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda R","family":"Yourick","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henoke","family":"Shiferaw","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim M","family":"Keppler-Noreuil","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene","family":"Elliot","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Rivas","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Garrett","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Gomez-Rodriguez","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil J","family":"Sebire","sequence":"additional","affiliation":[{"name":"Histopathology Department, Great Ormond Street Hospital NIHR Biomedical Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M","family":"Hewitt","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela L","family":"Schwartzberg","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,5,14]]},"reference":[{"key":"2019091012224851700_ref1","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1056\/NEJMoa1104017","article-title":"A mosaic activating mutation in AKT1 associated with the Proteus syndrome","volume":"365","author":"Lindhurst","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"2019091012224851700_ref2","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/gim.2017.65","article-title":"Quantifying survival in patients with Proteus syndrome","volume":"19","author":"Sapp","year":"2017","journal-title":"Genet. Med."},{"key":"2019091012224851700_ref3","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1002\/ajmg.a.37612","article-title":"Lack of mutation-histopathology correlation in a patient with Proteus syndrome","volume":"170","author":"Doucet","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"2019091012224851700_ref4","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/sj.ejhg.5201638","article-title":"The challenges of Proteus syndrome: diagnosis and management","volume":"14","author":"Biesecker","year":"2006","journal-title":"Eur. J. Hum. Genet."},{"key":"2019091012224851700_ref5","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O","article-title":"Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation","volume":"84","author":"Biesecker","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"2019091012224851700_ref6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/ajmg.a.30327","article-title":"Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases","volume":"130A","author":"Turner","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"2019091012224851700_ref7","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.jaad.2017.10.018","article-title":"Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome","volume":"78","author":"Nathan","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"2019091012224851700_ref8","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1002\/stem.1669","article-title":"Akt signaling leads to stem cell activation and promotes tumor development in epidermis","volume":"32","author":"Segrelles","year":"2014","journal-title":"Stem Cells"},{"key":"2019091012224851700_ref9","doi-asserted-by":"crossref","first-page":"10879","DOI":"10.1158\/0008-5472.CAN-07-2564","article-title":"Deregulated activity of Akt in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis","volume":"67","author":"Segrelles","year":"2007","journal-title":"Cancer Res."},{"key":"2019091012224851700_ref10","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1091\/mbc.e07-08-0764","article-title":"Constitutively active Akt induces ectodermal defects and impaired bone morphogenetic protein signaling","volume":"19","author":"Segrelles","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"2019091012224851700_ref11","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ydbio.2009.01.009","article-title":"Akt regulates skeletal development through GSK3, mTOR, and FoxOs","volume":"328","author":"Rokutanda","year":"2009","journal-title":"Dev. Biol."},{"key":"2019091012224851700_ref12","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1073\/pnas.0403198102","article-title":"Microvascular patterning is controlled by fine-tuning the Akt signal","volume":"102","author":"Sun","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2019091012224851700_ref13","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ccr.2006.07.003","article-title":"Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin","volume":"10","author":"Phung","year":"2006","journal-title":"Cancer Cell"},{"key":"2019091012224851700_ref14","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1093\/carcin\/bgl190","article-title":"Mice expressing myrAKT1 in the mammary gland develop carcinogen-induced ER-positive mammary tumors that mimic human breast cancer","volume":"28","author":"Blanco-Aparicio","year":"2007","journal-title":"Carcinogenesis"},{"key":"2019091012224851700_ref15","doi-asserted-by":"crossref","first-page":"17301","DOI":"10.18632\/oncotarget.8191","article-title":"Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis","volume":"7","author":"Mancini","year":"2016","journal-title":"Oncotarget"},{"key":"2019091012224851700_ref16","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.molmed.2018.08.003","article-title":"Cancer-associated PIK3CA mutations in overgrowth disorders","volume":"24","author":"Madsen","year":"2018","journal-title":"Trends Mol. Med."},{"key":"2019091012224851700_ref17","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1007\/BF00291899","article-title":"Cutaneous manifestation of lethal genes","volume":"72","author":"Happle","year":"1986","journal-title":"Hum. Genet."},{"key":"2019091012224851700_ref18","doi-asserted-by":"crossref","first-page":"1741072","DOI":"10.1155\/2016\/1741072","article-title":"Primordial germ cells: current knowledge and perspectives","volume":"2016","author":"Nikolic","year":"2016","journal-title":"Stem Cells Int."},{"key":"2019091012224851700_ref19","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1016\/j.celrep.2015.05.036","article-title":"Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo","volume":"11","author":"McGrath","year":"2015","journal-title":"Cell Rep."},{"key":"2019091012224851700_ref20","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1182\/blood-2003-03-0729","article-title":"Primary endothelial cells isolated from the yolk sac and para-aortic splanchnopleura support the expansion of adult marrow stem cells in vitro","volume":"102","author":"Li","year":"2003","journal-title":"Blood"},{"key":"2019091012224851700_ref21","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1001\/archderm.140.8.947","article-title":"Cutaneous manifestations of proteus syndrome: correlations with general clinical severity","volume":"140","author":"Nguyen","year":"2004","journal-title":"Arch. Dermatol."},{"key":"2019091012224851700_ref22","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1002\/ajmg.a.40636","article-title":"Characterization of the hepatosplenic and portal venous findings in patients with Proteus syndrome","volume":"176","author":"Takyar","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"2019091012224851700_ref23","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1002\/ajmg.a.37737","article-title":"Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis","volume":"170","author":"Keppler-Noreuil","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"2019091012224851700_ref24","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ajmg.1320570117","article-title":"Neoplasms in Proteus syndrome","volume":"57","author":"Gordon","year":"1995","journal-title":"Am. J. Med. Genet."},{"key":"2019091012224851700_ref25","first-page":"469","article-title":"Morphological characterization of the breast in Proteus syndrome complicated by ductal carcinoma in situ","volume":"36","author":"Iqbal","year":"2006","journal-title":"Ann. Clin. Lab. Sci."},{"key":"2019091012224851700_ref26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/ajmg.1320350228","article-title":"Proteus syndrome: course of a severe case","volume":"35","author":"Malamitsi-Puchner","year":"1990","journal-title":"Am. J. Med. Genet."},{"key":"2019091012224851700_ref27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1177\/0300985811430696","article-title":"Pathobiology of aging mice and GEM: background strains and experimental design","volume":"49","author":"Brayton","year":"2012","journal-title":"Vet. Pathol."},{"key":"2019091012224851700_ref28","doi-asserted-by":"crossref","first-page":"7202","DOI":"10.3402\/pba.v1i0.7202","article-title":"Practical pathology of aging mice","volume":"1","author":"Pettan-Brewer","year":"2011","journal-title":"Pathobiol. Aging Age Relat. Dis."},{"key":"2019091012224851700_ref29","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1177\/0300985813501334","article-title":"Neoplastic and nonneoplastic lesions in aging mice of unique and common inbred strains contribution to modeling of human neoplastic diseases","volume":"51","author":"Szymanska","year":"2014","journal-title":"Vet. Pathol."},{"key":"2019091012224851700_ref30","doi-asserted-by":"crossref","first-page":"1S","DOI":"10.1293\/tox.31.1S","article-title":"Nonproliferative and proliferative lesions of the rat and mouse endocrine system","volume":"31","author":"Brandli-Baiocco","year":"2018","journal-title":"J. Toxicol. Pathol."},{"key":"2019091012224851700_ref31","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nature05933","article-title":"A transforming mutation in the pleckstrin homology domain of AKT1 in cancer","volume":"448","author":"Carpten","year":"2007","journal-title":"Nature"},{"key":"2019091012224851700_ref32","volume-title":"Manipulating the Mouse Embryo: A Laboratory Manual","author":"Hogan","year":"1994"},{"key":"2019091012224851700_ref33","article-title":"R: A language and environment for statistical computing","author":"R Core Team","year":"2014"},{"key":"2019091012224851700_ref34","volume-title":"Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddz116\/28903521\/ddz116.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/17\/2920\/29207289\/ddz116.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T19:46:39Z","timestamp":1569267999000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/17\/2920\/5518346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,14]]},"references-count":34,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2019,5,14]]},"published-print":{"date-parts":[[2019,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz116","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,9,1]]},"published":{"date-parts":[[2019,5,14]]}}}