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

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...

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Published in:	PLoS genetics Vol. 13; no. 3; p. e1006683
Main Authors:	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, Lindsday A., Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, 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 Lourenço, 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.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 27.03.2017 Public Library of Science (PLoS)
Subjects:	Abnormalities, Multiple - genetics Abnormalities, Multiple - metabolism Abnormalities, Multiple - pathology Biology and Life Sciences Blood cancer Blotting, Western Cancer Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line Cell proliferation Cell Proliferation - genetics Cell Transformation, Neoplastic - genetics Child Child, Preschool Children & youth Craniofacial Abnormalities - genetics Craniofacial Abnormalities - metabolism Craniofacial Abnormalities - pathology Developmental disabilities Disruption Female Gene Expression Profiling Gene mutation Genetic aspects Genetic Association Studies Genetic Predisposition to Disease - genetics Genetics Genomes Genomics Germ-Line Mutation Hand Deformities, Congenital - genetics Hand Deformities, Congenital - metabolism Hand Deformities, Congenital - pathology Health sciences HEK293 Cells Hematologic Neoplasms - genetics Hematologic Neoplasms - metabolism Hematologic Neoplasms - pathology Hospitals Humans Incidence Infant Infant, Newborn Intellectual Disability - genetics Intellectual Disability - metabolism Intellectual Disability - pathology Laboratories Language Leukemia Life sciences Male Malignancy Medicine Medicine and Health Sciences Mutation Mutation hot spots Nails, Malformed - genetics Nails, Malformed - metabolism Nails, Malformed - pathology Neurosciences Nuclear Proteins - genetics Nuclear Proteins - metabolism Pathology Pediatrics Phenotype Research and Analysis Methods Schinzel-Giedion syndrome Netherlands Turkey United States > US Maryland Baltimore Maryland
ISSN:	1553-7404, 1553-7390, 1553-7404
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Summary:	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.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceptualization: RAH PD AH BWvB.Data curation: RAH PD SvD BWvB.Formal analysis: RAH PD CG BWvB.Funding acquisition: RAH LF JAV BBADV SEF.Investigation: RAH PD MSt JHF ABT ADe RS LAL HK UA EL MLU MA BGN EM LMAM VBF DDGH KMdR AJS ASB HR JSC AF MSm TAG NDD CD AV CML ADu ER GA AB CS JM AS BWvB.Methodology: RAH PD SAG BWvB.Project administration: SEF AH BWvB.Resources: MSt SAG JHF ABT ADe RS LAL HK UA EL MLU MA BGN EM LMAM VBF DDGH KMdR AJS ASB HR JSC AF MSm TAG NDD CD AV CML ADu ER GA AB CS JM BBADV AS SEF BWvB.Software: RAH CG SvD.Supervision: PD LF JAV BBADV AS SEF AH BWvB.Validation: RAH PD BWvB.Visualization: RAH BWvB.Writing – original draft: RAH BWvB.Writing – review & editing: RAH PD CG SvD JAV BBADV SEF AH BWvB. AH and BWvB also contributed equally to this work. The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1006683