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

• DOI: 10.1371/journal.pgen.1006683
• Publication Date: 2017-03-27T19:31:01Z
• Authors: Rocio Acuna-Hidalgo; Pelagia Deriziotis; Marloes Steehouwer; Christian Gilissen; Sarah A. Graham; Sipko van Dam; Julie Hoover-Fong; Aida B. Telegrafi; Anne Destree; Robert Smigiel; Lindsday A. Lambie; Hülya Kayserili; Umut Altunoglu; Elisabetta Lapi; Maria Luisa Uzielli; Mariana Aracena; Banu G. Nur; Ercan Mihci; Lilia M. A. Moreira; Viviane Borges Fe...; Dafne D. G. Horovitz; Katia M. da Rocha; Aleksandra Jezela...; Alice S. Brooks; Heiko Reutter; Julie S. Cohen; Ali Fatemi; Martin Smitka; Theresa A. Grebe; Nataliya Di Donato; Charu Deshpande; Anthony Vandersteen; Charles Marques L...; Andreas Dufke; Eva Rossier; Gwenaelle Andre; Alessandra Baumer; Careni Spencer; Julie McGaughran; Lude Franke; Joris A. Veltman; Bert B. A. De Vries; Albert Schinzel; Simon E. Fisher; Alexander Hoischen; Bregje W. van Bon
• Keywords: Degron

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS caused de novo germline mutations clustering to 12bp hotspot in exon 4 SETBP1. Mutations this disrupt degron, signal for the regulation protein degradation, lead accumulation SETBP1 protein. Overlapping have been observed recurrently as somatic events leukemia. We collected clinical information 47 patients (including 26 novel cases) with four individuals milder phenotype adjacent hotspot. Different within around varying effects on stability levels vitro silico modeling. Substitutions residue I871 result weak increase affecting are significantly more frequent than On other hand, substitutions D868 largest levels. Individuals enhanced cell proliferation higher incidence cancer compared mutations. Our findings substantiate that, despite their overlap, driving malignancy disruptive degron causing SGS. Additionally, suggests that functional threshold development driven disruption alteration prenatal Drawing previous studies leukemia, our results reveal genotype-phenotype correlation spanning molecular, cellular phenotype.