Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

dc.creatorAcuna-Hidalgo, Rocio
dc.creatorDeriziotis, Pelagia
dc.creatorSteehouwer, Marloes
dc.creatorGilissen, Christian
dc.creatorGraham, Sarah A.
dc.creatorvan Dam, Sipko
dc.creatorHoover-Fong, Julie
dc.creatorTelegrafi, Aida B.
dc.creatorDestree, Anne
dc.creatorSmigiel, Robert
dc.creatorLambie, Lindsday A.
dc.creatorKayserili, Hülya
dc.creatorAltunoglu, Umut
dc.creatorLapi, Elisabetta
dc.creatorUzielli, Maria Luisa
dc.creatorAracena, Mariana
dc.creatorNur, Banu G.
dc.creatorMihci, Ercan
dc.creatorMoreira, Lilia M. A.
dc.creatorBorges Ferreira, Viviane
dc.creatorHorovitz, Dafne Dain Gandelman
dc.creatorRocha, Katia M. da
dc.creatorJezela-Stanek, Aleksandra
dc.creatorBrooks, Alice S.
dc.creatorReutter, Heiko
dc.creatorCohen, Julie S.
dc.creatorFatemi, Ali
dc.creatorSmitka, Martin
dc.creatorGrebe, Theresa A.
dc.creatorDi Donato, Nataliya
dc.creatorDeshpande, Charu
dc.creatorVandersteen, Anthony
dc.creatorMarques Lourenço, Charles
dc.creatorDufke, Andreas
dc.creatorRossier, Eva
dc.creatorAndre, Gwenaelle
dc.creatorBaumer, Alessandra
dc.creatorSpencer, Careni
dc.creatorMcGaughran, Julie
dc.creatorFranke, Lude
dc.creatorVeltman, Joris A.
dc.creatorDe Vries, Bert B. A.
dc.creatorSchinzel, Albert
dc.creatorFisher, Simon E.
dc.creatorHoischen, Alexander
dc.creatorvan Bon, Bregje W.
dc.date2021-01-06T19:42:43Z
dc.date2021-01-06T19:42:43Z
dc.date2017
dc.date.accessioned2023-09-26T20:14:07Z
dc.date.available2023-09-26T20:14:07Z
dc.identifierAcuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LM, Borges Ferreira V, Horovitz DD, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenço C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BB, Schinzel A, Fisher SE, Hoischen A, van Bon BW. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genet. 2017 Mar 27;13(3):e1006683. doi: 10.1371/journal.pgen.1006683. PMID: 28346496; PMCID: PMC5386295.
dc.identifier1553-7390
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/45518
dc.identifier10.1371/journal.pgen.1006683
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8852094
dc.descriptionSchinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
dc.formatapplication/pdf
dc.languageeng
dc.publisherPublic Library of Science [Commercial Publisher]
dc.rightsopen access
dc.subjectAbnormalities, Multiple / genetics
dc.subjectAbnormalities, Multiple / metabolism
dc.subjectAbnormalities, Multiple / pathology
dc.subjectBlotting, Western
dc.subjectCarrier Proteins / genetics
dc.subjectCarrier Proteins / metabolism
dc.subjectCell Line
dc.subjectCell Proliferation / genetics
dc.subjectCell Transformation, Neoplastic / genetics
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectCraniofacial Abnormalities / genetics
dc.subjectCraniofacial Abnormalities / metabolism
dc.subjectCraniofacial Abnormalities / pathology
dc.subjectFemale
dc.subjectGene Expression Profiling
dc.subjectGenetic Association Studies
dc.subjectGenetic Predisposition to Disease / genetics
dc.subjectGerm-Line Mutation
dc.subjectHEK293 Cells
dc.subjectHand Deformities, Congenital / genetics
dc.subjectHand Deformities, Congenital / metabolism
dc.subjectHand Deformities, Congenital / pathology
dc.subjectHematologic Neoplasms / genetics
dc.subjectPhenotype
dc.subjectNuclear Proteins / metabolism
dc.subjectHematologic Neoplasms / metabolism
dc.subjectHematologic Neoplasms / pathology
dc.subjectNuclear Proteins / genetics
dc.subjectNails, Malformed / pathology
dc.subjectNails, Malformed / metabolism
dc.subjectNails, Malformed / genetics
dc.subjectMutation
dc.subjectMale
dc.subjectHumans
dc.subjectInfant
dc.subjectIntellectual Disability / pathology
dc.subjectIntellectual Disability / genetics
dc.subjectInfant, Newborn
dc.titleOverlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
dc.typeArticle


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