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

Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A., van Dam, Sipko, Hoover-Fong, Julie, Telegrafi, Aida B., Destree, Anne, Smigiel, Robert, Lambie, Lindsay A., Kayserili, Hulya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria L., Aracena, Mariana, Nur, Banu G., Mihci, Ercan, Moreira, Lilia M. A., Borges Ferreira, Viviane, Horovitz, Dafne D. G., da Rocha, Katia M., Jezela-Stanek, Aleksandra, Brooks, Alice S., Reutter, Heiko, Cohen, Julie S., Fatemi, Ali, Smitka, Martin, Grebe, Theresa A., Di Donato, Nataliya, Deshpande, Charu, Vandersteen, Anthony, Marques Lourenco, Charles, Dufke, Andreas, Rossier, Eva, Andre, Gwenaelle, Baumer, Alessandra, Spencer, Careni, McGaughran, Julie, Franke, Lude, Veltman, Joris A., De Vries, Bert B. A., Schinzel, Albert, Fisher, Simon E., Hoischen, Alexander and van Bon, Bregje W. (2017) Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genetics, 13 3: . doi:10.1371/journal.pgen.1006683

Author Acuna-Hidalgo, Rocio
Deriziotis, Pelagia
Steehouwer, Marloes
Gilissen, Christian
Graham, Sarah A.
van Dam, Sipko
Hoover-Fong, Julie
Telegrafi, Aida B.
Destree, Anne
Smigiel, Robert
Lambie, Lindsay A.
Kayserili, Hulya
Altunoglu, Umut
Lapi, Elisabetta
Uzielli, Maria L.
Aracena, Mariana
Nur, Banu G.
Mihci, Ercan
Moreira, Lilia M. A.
Borges Ferreira, Viviane
Horovitz, Dafne D. G.
da Rocha, Katia M.
Jezela-Stanek, Aleksandra
Brooks, Alice S.
Reutter, Heiko
Cohen, Julie S.
Fatemi, Ali
Smitka, Martin
Grebe, Theresa A.
Di Donato, Nataliya
Deshpande, Charu
Vandersteen, Anthony
Marques Lourenco, Charles
Dufke, Andreas
Rossier, Eva
Andre, Gwenaelle
Baumer, Alessandra
Spencer, Careni
McGaughran, Julie
Franke, Lude
Veltman, Joris A.
De Vries, Bert B. A.
Schinzel, Albert
Fisher, Simon E.
Hoischen, Alexander
van Bon, Bregje W.
Title Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
Formatted title
Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7404
Publication date 2017-03-27
Year available 2017
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1006683
Open Access Status DOI
Volume 13
Issue 3
Total pages 25
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2018
Language eng
Formatted abstract
Schinzel-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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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